Oil and liquid silicone foamable carriers and formulations

ABSTRACT

A waterless foamable pharmaceutical composition suitable for external administration is disclosed. The composition includes a foamable carrier least one liquefied or compressed gas propellant. The foamable carrier includes at least one liquid oil; at least one silicone and at least one least one stabilizing agent; wherein the stabilizing agent selected from the group consisting of about 0.01% to about 25% by weight of at least one surface-active agent alone or on combination with a foam adjuvant; and about 0% to about 5% by weight of at least one polymeric agent alone or on combination with a foam adjuvant; and mixtures thereof. Pharmaceutical compositions comprising active agents, methods for their preparation, propellants suitable for use with the carriers and uses thereof are further described.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation under 35 U.S.C. §120 ofPCT/IB2008/03939, filed on Dec. 8, 2008, which claims priority under 35U.S.C. §119(e) of U.S. Provisional Patent Application No. 61/012,414,filed on Dec. 7, 2007, entitled “Carriers, Formulations, Methods ForFormulating Unstable Active Agents For External Application And UsesThereof,” and U.S. Provisional Patent Application No. 61/103,500, filedon Oct. 7, 2008 entitled “Oil and Liquid Silicone Carriers andFormulations for External and Body Cavity Application of Active Agentsand Uses Thereof.”

FIELD

This invention relates to waterless foam formulations, specificallysingle phase foamable composition including silicone. The inventionfurther relates to methods for formulating stable and unstable activeagents in topical compositions, which are suitable, inter alia, forapplying to the skin or to mucosal surfaces and can be used for treatingtopical, mucosal and/or systemic disorders in mammals. The inventionfurther relates to vehicles which are suitable, inter alia, for deliveryfor a wide range of active pharmaceutical and cosmetic agents andmethods for their use.

BACKGROUND

External topical administration is an important route for theadministration of drugs in both systemic and topical disease treatment.For example, diseases of the skin, such as inflammatory diseases (e.g.,acne), rashes, infection (e.g., microbial infection and parasiticinfestation), and immune system reactions leading to rashes and/orinfection, are typically treated via topical administration of apharmaceutical active agent. Many drugs that may be useful for topicaladministration (e.g., antibiotics, anti-fungal agents, anti-inflammatoryagents, anesthetics, analgesics, anti-allergic agents, corticosteroids,retinoids and anti-proliferative medications) are preferablyadministered in hydrophobic media, such as a petrolatum-based ointmentor a cream, due to their increased stability in hydrophobic solvents.While the use of stabilizers, anti oxidants antimicrobial preservatives,buffers and the like in aqueous compositions to protect active orcosmetic agents is known, there are still disadvantages to formulatingcertain active agents in aqueous compositions, or even in compositionscontaining low amounts of polar solvents such as water (e.g., water inoil emulsions). For example, some active agents are known to begenerally unstable or susceptible to isomerisation or to breakdown inthe presence of water, resulting in loss of activity. Thus, in severalcases, many drugs are more soluble or more stable in hydrophobicsolvents; and therefore, the development of simple and elegantformulations to accommodate and stabilize active ingredients in ahydrophobic waterless or substantially waterless environment isdesirable.

However, hydrophobic formulations, in particular ointments, also posedisadvantages to topical administration. For example, ointments oftenform an impermeable barrier. In the treatment of a topical wound, such abarrier would prevent the removal or draining of metabolic products andexcreta from these wounds. Moreover, the efficacy of drugs formulated inointments is compromised because of the difficulty for an active drugdissolved in an ointment-based carrier to pass through the barrier layerinto the wound tissue. In addition, ointments and creams often do notcreate an environment for promoting respiration of wound tissue ornormal respiration of the skin. An additional disadvantage of ointmentformulations is the greasy feeling left following their topicalapplication onto the skin, mucosal membranes and wounds.

Formulations based on hydrophobic media also include those based on oilsor hydrophobic emollient vehicles. These formulations have a number ofuseful attributes making them suitable candidates for topicalpharmaceutical and cosmetic compositions, including foamablecompositions. They are inherently stable and inert which are clearlydesirable characteristics. They are able to condition the skin and inappropriate amounts can form a barrier to skin moisture loss. Byappropriate formulation they can act to improve drug delivery to theskin and yet remain resistant to being washed off. On the other hand,they are by their nature greasy materials and can be difficult toformulate particularly into a topical foamable composition that candeliver a substantially uniform and stable composition or foam thatameliorates or overcomes the look and feel of a greasy material,especially where that composition is waterless or substantially so. Itis further a problem to incorporate into such a vehicle pharmaceuticallyeffective amounts of one or more active pharmaceutical ingredients suchthat they are uniformly present throughout the formulation and areeffectively delivered without the use of an alcohol in the formulation.

Foamable compositions offer advantages over ointments and creams fortopical administration of pharmaceuticals. While hydrophobic foamablecompositions are known, it is far from simple or obvious to producehydrophobic waterless foamable compositions that when released producefoams of quality suitable for pharmaceutical or cosmetic application. Ona further level, having realized a carrier that will produce ahydrophobic waterless foam of quality there is an additional difficultyto be overcome, namely how to adapt the formula and achieve a uniformformulation, which can accept a range of various active pharmaceuticaland cosmetic agents such that the composition and active agent arestable and the foam produced remains of quality. Specifically, one ofthe challenges in preparing such waterless or substantially waterlessfoamable compositions is ensuring that the active pharmaceutical ortherapeutic agent does not react, isomerize or otherwise break down toany significant extent during is storage and use. Particularly, thereremains an unmet need for improved, easy to use, stable andnon-irritating foam formulations, with unique therapeutic or beneficialproperties containing a stable or stabilized active pharmaceutical orcosmetic agent.

Silicones are hydrophobic substances that offer unique cosmeticproperties. They are tasteless, essentially odorless, non-greasy andnon-stinging; they are used as a base fluid in many personal careproducts, with excellent spreading and easy rubout and lubricationproperties. Volatile silicone compounds are a specific class ofsilicones, used in dermal formulations to condition the skin, whilereducing the greasy feel of other oils in the formulation. However, oneof the principal hindrances to the use of silicones in foam formulationsis their known antifoaming effect, especially when included in theformulation in substantial quantities. More specifically, silicones areknown for being efficient foam control agents and can prevent foamformation or cause foam to collapse rapidly. Silicone fluids can, forexample, enter into the foam lamella and displace the foam stabilizingsurfactants from the interphase. The foam lamellas are thereforedestabilized and burst resulting in foam collapse. Thus, silicones areessentially contra-indicated for the preparation of foamable carriersand compositions. Nevertheless, because of the favorable properties ofsilicones, there is still an unmet need to develop foamable formulationsincorporating silicone that can produce easy to use good quality foam,especially in substantial quantities.

In general terms foam formed from hydrophobic waterless or substantiallywaterless compositions may by their inherent nature be less firm orinherently weaker than water based emulsion compositions. Thus, not onlyare silicones inherently unsuitable for forming foamable compositionsbut it may additionally go against the grain to try and use them inwaterless compositions.

US Patent Publication No. 2008/0031908 describes an aerosol productcontaining an oily composition containing at least one oil, and at leastone hydrocarbon compound (notably, a paraffin or a fatty acid amide)having a melting point greater than or equal to 30° C. (i.e., a solid atroom temperature), the compound being in the form of solid particles andone or more propellants. Hydrocarbon solid particles were required toprovide a fine bubble, stable foam.

US Patent Publication No. 2005/0287081 (corresponding to InternationalPatent Publication No. WO 2006/031271) describes a topicalpharmaceutical aerosol foam containing high levels of liquid siliconesto enhance cosmetic elegance, containing five essential ingredients: (1)a lipophilic compound or combinations of lipophilic compounds; (2) aliquid silicone or a combination of liquid silicones; (3) a foamingagent, which is selected from the group consisting of mono, di, triesters of sorbitol and fatty acids; (4) an active agent; and (5) apropellant. The formulations described in the publication contain lessthan 60% liquid oil and significant levels of liquid silicone,indicating that foamable compositions containing very high levels ofliquid oil were not achieved. Notably, the foam product of theformulations described in US 2005/0287081 is prone to collapse quicklyas illustrated below in the Examples, which is also undesirable for atopical foam formulation.

U.S. Pat. No. 3,770,648 teaches that solid silicone resin must bepresent in quantities to produce a quick breaking anhydrous foam.

Foams are complex dispersion systems which do not form under allcircumstances. Slight shifts in foam composition, such as by theaddition of active ingredients, may destabilize the foam. Foams are verycomplex and sensitive systems and are not formed at will. Mere additionof basic ingredients like oil, surfactant and propellant is far fromsufficient to produce foams of quality that are homogenous, stable,breakable upon mechanical force and can be used to provide a shelfstable pharmaceutical or cosmetic composition. Small deviations may leadto foam collapse. Much consideration needs to be given to facilitate theintroduction of an active agent, such as examining compatibility and nonreactivity with the various excipients and container and determiningshelf life chemical stability.

Neubourg (US 2006/0099151), for example, notes that the stability offoam is strongly dependent on the specific composition of the foamforming components, so that even small deviations in the composition maylead to a collapse of the foam. Gordon et al. (U.S. Pat. No. 3,456,052).also teaches that one cannot generate a good quality foam by simplyadding a propellant to a mixture of components:

The term “foam” is a general term that encompasses a range ofsubstances. Accordingly, the context in which “foam” is discussed mustbe examined carefully. The type and quality of the foam is of criticalimportance. There are many different types of foams and within each foamtype there are many levels of qualities. For example, the froth on thehead of beer, lather of shampoo, and lather of shaving cream have beenloosely described as foam but all are different from one another. At oneend of the cosmetic or pharmaceutical foam spectrum the foam can be longlasting and essentially not readily breakable like shaving foams. At theother end of the spectrum the foam can be quick breaking and collapsesupon release.

Thermolabile foams are an example of type of quick breaking foam. Theycan contain significant amounts of thermolabile substances that aidtheir collapse upon being exposed to an increased temperature forexample when applied to a body surface at 37 C. Upon being exposed tothe higher temperature they collapse rapidly. Examples are foamformulations that comprise significant amounts of volatile solvents.

Breakable foam is a specialized type of foam. It is a low density foamthat is stable on release at least in the short time span of severalminutes, which facilitates application to a target area; but can breakreadily upon the application of shear force such as gentle rubbing tospread easily over a target surface. It is not thermolabile (and doesnot melt at skin temperature) and nor does it display late or longdelayed expansion over minutes. In some embodiments, the compositionsdescribed herein produce breakable foams.

Some foams expand slowly whilst others do so quickly. Some foams foamimmediately and some demonstrate delayed foaming. Some requiremechanical lathering and some expulsion by propellant. Whilst they allfall under the so called term “foam” and may appear to have some commoningredients the results and properties of these products are different.

A suitable foamable formulation for a particular application may presentchallenges at several levels. For example, a foam formulation mayrequire a stable pre foam formulation; a stable pre foam propellantformulation (e.g., a foamable carrier) and ultimately delivery aneffective measured amount of active agent to a target. Each of theseobjectives poses its own unique challenges.

The pharmaceutical and cosmetic foams discussed herein are generated ingeneral terms by manufacturing a suitable foamable carrier compositionand loading the carrier in a pressurized valved canister with anappropriate propellant. Upon expelling the canister contents a foam canbe released. The type, nature and quality of the foam depends inter aliaon the carrier composition, the active agent, the propellant and themethod of manufacture and storage. Making a stable (physically andchemically) formulation that can be stored in a canister with apropellant that remains stable and can produce a breakable foam ofquality on release is far from trivial.

An additional difficulty frequently encountered with propellant foams istheir inability to dispense a uniform application of the medicallyactive ingredient throughout the use of the entire aerosol container.This is particularly due to the fact that the active material is notstably dispersed in the foamable composition so that it will have atendency to settle to the bottom. Further, the dispersed material willsometimes clog the spray dispensing valve to further interfere with theuniform dispensing of the medicament.

SUMMARY

There remains an unmet need for improved, easy to use, stable andnon-irritating oil based foam formulations, with unique physical,therapeutic or beneficial properties containing a stable or stabilizedactive pharmaceutical or cosmetic agent. Moreover, there is an unmetneed for waterless and substantially oil based waterless carriers andfoam formulations with liquid silicone, which have a good or specialskin feeling and which provide many of the desirable attributes of waterbased emulsions and foams, such as pleasant feeling, absence ofstickiness, good spreadability, relatively quick absorption, absence ofshine and reduced oily sensation

Compositions formulated using a base comprising an oil combined withliquid silicones to produce waterless formulations are investigated anddeveloped herein as pharmaceutical and cosmetic waterless carrierssuitable for delivery of a wide range of active agents despite thedefoaming properties of silicones. In particular, such carriers that aresubstantially a single phase and, in some embodiments, are substantiallyfree of particles. Moreover such carriers are ideal for oil solubleactive agents and can nevertheless carry as a homogenous suspensionsubstantial amounts of oil insoluble active agents.

In one aspect, a waterless foamable pharmaceutical composition includinga foamable carrier and at least one liquefied or compressed gaspropellant is disclosed. The foamable carrier includes: (i) about 60% toabout 95% by weight of at least one liquid oil; (ii) a silicone; and(iii) at least one foam stabilizing agent. The foamable carrier issubstantially a single phase. The foam stabilizing agent is selectedfrom the group consisting of about 0.01% to about 25% by weight of atleast one surface-active agent alone or in combination with a foamadjuvant; about 0% to about 5% by weight of at least one polymeric agentalone or in combination with a foam adjuvant and mixtures thereof. Theratio of the foamable carrier to the propellant is 100:03 to 100:35.

In some embodiments, the waterless foamable pharmaceutical compositionincludes, by weight: (i) about 60-90% mineral oil; (ii) about 1-15% ofone or more of cyclomethicone; a mixture of cyclohexasiloxane andcyclopentasiloxane, cyclytetrasiloxane, dimethiconol, phenyltrimethicone, stearyl dimethicone or mixtures thereof; (iii) about 1-8%glycerol monostearate; and (iv) about 1-8% myristyl alcohol orcetostearyl alcohol; and the composition is essentially free of water.

In another aspect, a waterless foamable pharmaceutical composition isprovided. The composition includes a foamable carrier and at least oneliquefied or compressed gas propellant. The foamable carrier includes:

-   a) about 60% to about 95% by weight of at least one liquid oil;-   b) a silicone; and-   c) about 0.01% to about 25% by weight of a monoglyceride,    diglyceride, or triglyceride, or a mixture thereof, wherein the side    chain of the monoglyceride, diglyceride, or triglyceride is a    saturated hydrocarbon.    The foamable carrier is substantially a single phase; and the ratio    of the foamable carrier to the propellant is 100:03 to 100:35.

According to some embodiments, the fatty acid side chain of themonoglyceride, diglyceride, or triglyceride, or a mixture thereof,contains at least 8 carbon atoms. According to some embodiments, themonoglyceride, diglyceride, or triglyceride, or a mixture thereof, is astearic-acid derived ester. According to some embodiments, themonoglyceride, diglyceride, or triglyceride, or a mixture thereof isglycerol monostearate or glycerol palmitostearate.

In some embodiments, the silicone used in the compositions describedherein is a cyclic silicone, a branched silicone, a polar silicone or amixture thereof. Exemplary cyclic silicones include, without limitationsiloxane compounds having 4-6 Si—O groups in its backbone. In someembodiments, the cyclic silicone is a cyclomethicone. Exemplary branchedsilicones include, without limitation, phenyl trimethicone, stearylmethicone, cetyl dimethicone, caprylyl methicone, PEG/PPG 18/18dimethicone, and mixtures thereof. Exemplary polar silicones include,without limitation dimethiconol or PEG/PPG 18/18 dimethicone

In some embodiments, the at least one liquid oil used in thecompositions described herein comprises mineral oil. Nonlimitingexamples of oils for use in the foamable carriers described hereininclude mineral oil, MCT oil, liquid paraffin, vegetable oil, essentialoil, organic oil, lipid, or a mixture thereof. In some embodiments, theoil is a mixture of light mineral oil and heavy mineral oil. In someembodiments, the weight ratio of the heavy mineral oil to the lightmineral oil ranges from about 1:5 to about 25:1.

In some embodiments, the foamable carriers described herein furthercomprise an emollient. Examples of emollients for use in thecompositions described herein include, without limitation, coglycerides,PPG 15 stearyl alcohol, octyldodecanol, isopropyl myristate, diisopropyladipate, cetearyl octanoate isohexadecanol, diisopropyl adipate andmixtures thereof.

In some embodiments, the foamable carriers described herein furthercomprise a solid wax or solid oil. Exemplary solid wax or oil include,without limitation solid paraffin, hydrogenated oil, hydrogenatedemollient, palmitic acid, stearic acid, arachidic acid, behenic acid andmixtures thereof.

In some embodiments, the foam adjuvant used in the compositionsdescribed herein is a solid. Nonlimiting examples of solid foamadjuvants include a solid fatty alcohol selected from the groupconsisting of stearyl alcohol, cetyl alcohol, cetostearyl alcohol,myristyl alcohol, palmitoleyl alcohol, arachidyl alcohol, benzyl alcoholand mixtures thereof. In some embodiments, the foam adjuvant comprisesoleyl alcohol.

In some embodiments, the surface active agent used in the compositionsdescribed herein is a stearic acid derived ester. In other embodiments,the surface active agent is monoglyceride, diglyceride, or triglyceride,wherein the side chain of the monoglyceride, diglyceride, ortriglyceride is a C8-C24 saturated hydrocarbon. Exemplary surface activeagents include, without limitation, glycerol monostearate, glycerolpalmitostearate, PEG 100 Stearate, Montanov L, Montano 68, PPG 15stearyl ether or a mixture thereof.

In some embodiments, the surface active agent used in the compositionsdescribed herein is a solid.

In some embodiments, the weight ratio of surface active agent tosilicone in the compositions described herein ranges from about 1:1 toabout 1:4.

In some of the compositions described herein, (i) the liquid oilconsists essentially of mineral oil; (ii) the silicone is present in thefoamable carrier in an amount of about 0.5% to about 15% by weight; and(iii) the at least one stabilizing agent is glycerol monostearate and ispresent in the foamable carrier in an amount of about 0.01% to 25% byweight.

In some embodiments the waterless foamable pharmaceutical compositionsdescribed above also include an active agent. In some embodiments, theactive agent is soluble in the liquid oil, the silicone, the surfactantor the composition. In some embodiments, the foamable carrier includingthe active agent forms a substantially homogenous suspension.

Exemplary active agents include active herbal extracts, acaricides, agespot and keratose removing agents, allergen, analgesics, localanesthetics, antiacne agents, antiallergic agents, antiaging agents,antibacterials, antibiotic agents, antiburn agents, anticancer agents,antidandruff agents, antidepressants, antidermatitis agents,antiedemics, antihistamines, antihelminths, antihyperkeratolyte agents,antiinflammatory agents, antiirritants, antilipemics, antimicrobials,antimycotics, antiproliferative agents, antioxidants, anti-wrinkleagents, antipruritics, antipsoriatic agents, antirosacea agentsantiseborrheic agents, antiseptic, antiswelling agents, antiviralagents, anti-yeast agents, astringents, topical cardiovascular agents,chemotherapeutic agents, corticosteroids, dicarboxylic acids,disinfectants, fungicides, hair growth regulators, hormones, hydroxyacids, immunosuppressants, immunoregulating agents, insecticides, insectrepellents, keratolytic agents, lactams, metals, metal oxides,mitocides, neuropeptides, non-steroidal anti-inflammatory agents,oxidizing agents, pediculicides, photodynamic therapy agents, retinoids,sanatives, scabicides, self tanning agents, skin whitening agents,vasoconstrictors, vasodilators, vitamins A, B, C, D, E and K and theirderivatives, wound healing agents, wart removers and mixtures thereof.

In some embodiments, the active agent is a tetracycline antibioticagent. Exemplary tetracycline antibiotic agents include, withoutlimitation minocycline or doxycycline.

Nonlimiting examples of active agents include acyclovir, azaleic acid,clindamycin phosphate, pimicrolimus, diclofenac potassium; calcipotriol,calcitriol, vitamin A acetate, betamethasone 17-valerate, alphatocopherol, imiquimod, ciclopiroxolamine, and mixtures thereof.

A method of delivering an active agent to a patient in need oftreatment, the method including administering a foamable pharmaceuticalcomposition described herein to a skin surface, a mucosal surface, or abody cavity is also disclosed.

A method for treating skin or a mucosal surface including administeringto the skin or mucosal surface a pharmaceutically effective amount of afoamable pharmaceutical composition described herein is disclosed.

A method for treating, ameliorating or preventing a disorder includingadministering to a target site a pharmaceutically effective amount of afoamable pharmaceutical composition described herein is disclosed. Insome embodiments, the methods for treatment described herein include acombination of at least two active agents. In some embodiments, thetarget site is selected from the group consisting of the skin, a bodycavity, a mucosal surface, the nose, the mouth, the eye, the ear canal,the respiratory system, the vagina and the rectum.

In some embodiments, the waterless foamable pharmaceutical compositionsdescribed herein produce a resultant foam that displays all of thefollowing characteristics

a. at least of good quality;

b. does not collapse immediately upon release;

c. is breakable on mechanical shear;

d. has a density below about 0.2 g/ml; and

e. has a collapse time in excess of about 180 seconds.

In some embodiments, the waterless foamable pharmaceutical compositionsdescribed herein produce a resultant foam that displays all of thefollowing characteristics:

a. at least of good quality;

b. does not collapse immediately upon release;

c. is breakable on mechanical shear;

d. has a viscosity below about 13,000 cps;

e. has an average bubble size below 200 microns;

f. has a hardness between about 5 to about 35 and

e. has a collapse time in excess of about 180 seconds.

In another aspect, a method for preparing a substantially single phase,waterless foamable pharmaceutical composition is provided. The methodincludes the steps of:

-   -   (a) combining about 60% to about 95% by weight of at least one        liquid oil with at least one foam stabilizing agent at a        temperature of at least about 50° C.;    -   (b) rapidly cooling the combination of one liquid oil and at        least one foam stabilizing agent to less than 40° C.;    -   (c) adding a silicone to the cooled combination to make a        prefoam formulation; and    -   (d) combining the prefoam formulation with a compressed gas        propellant in a weight ratio of 100:3 to 100:35.        In the method described above, the foam stabilizing agent is        selected from the group consisting of about 0.01% to about 25%        by weight of at least one surface-active agent alone or in        combination with a foam adjuvant; about 0% to about 5% by weight        of at least one polymeric agent alone or in combination with a        foam adjuvant and mixtures thereof. The method for preparing a        substantially single phase, waterless foamable pharmaceutical        composition is useful for preparing the pharmaceutical        compositions and foamable carriers described herein.

In another aspect, a method for preparing a substantially single phase,waterless foamable pharmaceutical composition is provided. The methodincludes the steps of:

-   -   (a) preparing a prefoam formulation by combining at a        temperature of at least about 50° C.:    -   about 60% to about 95% by weight of at least one liquid oil; a        silicone; and at least one foam stabilizing agent;    -   (b) rapidly cooling the prefoam formulation to less than 40° C.;        and    -   (c) combining the prefoam formulation with a compressed gas        propellant in a weight ratio of 100:3 to 100:35.        The foam stabilizing agent is selected from the group consisting        of about 0.01% to about 25% by weight of at least one        surface-active agent alone or in combination with a foam        adjuvant; about 0% to about 5% by weight of at least one        polymeric agent alone or in combination with a foam adjuvant and        mixtures thereof.

In some embodiments of the preparation methods described herein, thecooling step is carried out by placing the combination of one liquid oiland at least one foam stabilizing agent in an ice bath, in an alcoholwater bath or in a water bath or jacket.

In some embodiments of the preparation methods described herein, thecombination of one liquid oil and at least one foam stabilizing agent iscooled at a rate of at least about 5 degrees/minute.

In some embodiments of the preparation methods described herein, thecombination of one liquid oil and at least one foam stabilizing agent iscooled to a temperature of at least about 25° C.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a color photograph of the foamable carrier prepared accordingto Example 22G.

DETAILED DESCRIPTION

Oil-based, foamable compositions containing silicone are describedherein. Surprisingly, the silicone containing compositions aresingle-phase and exhibit good stability. While oil-based foams are knownin the art, it is generally understood that these foams are highlyunstable. For example, oil-based foams typically drain shortly afterdispensing (e.g., 20-30 seconds following dispensing), leading tosubsequent collapse of the foam. Accordingly, oil-based foams areconsidered to lack stability and are not considered suitable for manyuses, including as pharmaceutical compositions for topicaladministration. In contrast, the oil based foamable compositionsdescribed herein generate foams that exhibit excellent stability, asdemonstrated by prolonged time to collapse. For example, the foamgenerated from the compositions described herein is at least short termstable and can be resilient to collapse for at least 2-3 minutes andfrequently for 5 minutes after dispensing, at 36° C.

Moreover, the oil-based foamable compositions described herein aresingle phase compositions. It is conventionally understood in the artthat good quality foams require the use of an emulsion. Exemplaryemulsions typically used to produce foams include oil-in-water andwater-in-oil emulsions. The foamable compositions described herein,however, are single-phase compositions, exhibiting minimal or nopartitioning between phases. As a result, the foamable compositions, aswell as the resulting foams, are substantially uniform. Thus, activeagents are suspended or dissolved uniformly in the foams produced fromthe compositions, and there is no concern that the active agent isconcentrated in a particular phase.

It was unexpectedly observed that quality foams with an oil/silicone oilbased single phase waterless formulation are produced when one or moreof the following conditions are met:

-   -   I. Presence of three ingredients: oil, surfactant and silicone,        as a single phase. In a particular embodiment the surfactant is        glycerol monostearate, alone or glycerol palmitostearate alone        or either one in combination with PEG 100 stearate.    -   II. A silicone which is capable of generating stearic hindrance        or molecular repulsion between itself and the oil/surfactant        structure. Unexpectedly, the structure of silicone appears to be        highly significant to the creation of stable foams.    -   III. A ratio between surfactant and silicone ranging from about        1:1 to about 1:4, such as about 1:1; about 4:5; about 1:2; about        3:5; about 1:3; about 2:5 and about 1:4 and any ratio between        any of the aforesaid ratios.    -   IV. In certain embodiments, rapid cooling of the compositions        during their preparation is important improve foam quality. When        rapid cooling is used, in contrast with slow cooling, it        frequently results in a clear improvement of foam quality. In        some highly complex formulations with many excipients the        advantages of fast cooling are more subtle and can be reflected        in parameters like viscosity, appearance and foam quality.    -   V. Preparing the foamable composition using both slow and rapid        cooling procedures resulted in high quality foam.

In certain embodiments the concentration of the surfactant, the oil andthe silicone and any other ingredients should be selected so that thecomposition, after filling into aerosol canisters, is flowable, and canbe shaken in the canister. In one or more embodiments, the concentrationof the surfactant, the oil and the silicone are selected such that theviscosity of the composition, prior to filling of the composition intoaerosol canisters, is less than 13,000 CPs, and more preferably, lessthan 10,000 CPs, preferably below about 9000, more preferably belowabout 6000 cps. In one or more embodiments the concentration of thesurfactant, the oil and the silicone and any other ingredients should beselected so that the composition produces a foam of quality preferablyat least about of good quality. In one or more embodiments, theconcentrations of the surfactant, the oil and the silicone are selectedsuch that the average bubble size should be below about 200 microns,preferably below 150 and more preferably below 100 microns. In one ormore embodiments, the concentrations of the surfactant, the oil and thesilicone are selected such that the foam density is below about 0.2 andpreferably below about 0.1 g/ml or in the range of about 0.07 to about1.5 g/ml. In one or more embodiments, the concentrations of thesurfactant, the oil and the silicone are selected such that the foamhardness in the range of about 5 to about 35. In one or more embodimentsthe foam is of at least about good quality, the bubble size is below 150microns and the density is between 0.07 and 1.5.

In certain embodiments the concentration of the oil is mineral oil, Inone or more embodiments the mineral oil is a mixture of mineral oils. Incertain embodiments the mixture is a mixture of light and heavy mineraloils. In one or more embodiments the ratio of heavy to light mineral oilis from about 1:5; about 2:5, about; 5:11; about 1:2; about: 4:7; about3:5; about 2:3; about 3:4; about; 5:6; about 1:1; about 6:5; about 4:3;about 3:2; about 5:3; about 7:4; about 2:1; about 11:5; about 5:2; about5:1; about 10:1; about 15:1; about 20:1 and about 25:1 and any ratiobetween any of the aforesaid ratios. In one or more embodiments theratio range of heavy to light mineral oil is from about 1:5 to about25:1; and preferably in the range of about 2:5 to about 5:1.

Without wishing to be bound by a particular theory, it is believed thatin certain embodiments oil-based foams are stabilized by the presence ofa silicone in the foamable composition. In particular, the silicone ispresent in the composition in combination with a high concentration ofliquid oil (greater than about 60%) and a stabilizing agent. In generalterms in preparing the formulation the oil and surfactant are typicallyfirst combined and then the silicone is introduced. It is thought,without being bound by any theory, that silicones having the ability togenerate stearic hindrance are less able to penetrate the alreadyestablished surfactant/oil structure. Accordingly, it is thought thatthese types of silicones have a diminished destabilizing effect on theresulting foam composition than silicones that are able to penetrate theintermingled chains of the surfactant/oil structure. It follows that byselecting silicones that are better able to generate stearic hindrancesuch silicones are more likely to have a lesser destabilizing effect andvice versa. Thus, in one embodiment, the silicone is a cyclic silicone.In a further embodiment, the silicone includes hydrophobic side chains.

In a further aspect, it is thought that molecular repulsion plays a rolein the stabilizing effect, either alternatively or in addition to therole of stearic hindrance. Silicones which are less likely to berepulsed by the surfactant oil/structure are more likely to destabilizethe surfactant/oil structure and vice versa. So for example siliconeswith hydrophilic (e.g., polar) moieties are more likely to repulsehydrophobic oil and/or hydrophobic side chains of some surfactants, suchas monoglycerides (e.g., glycerol monostearate). Accordingly, in one ormore preferred embodiments the silicone is a branched chain silicone ora silicone having one or more hydrophilic or polar moieties.

In a particular embodiment, the silicone is cyclomethicone,cyclotetrasiloxane, cyclohexasiloxane, dimethiconol, phenyltrimethicone,or stearyl dimethicone.

Thus, the oil-based foams in certain embodiments are believed to bestabilized by the presence of a cyclic silicone and/or a linear highlysubstituted silicone in the foamable composition. The cyclic silicone ispresent in the composition in combination with a high concentration ofliquid oil (e.g., greater than about 60%) and a stabilizing agent. Insome embodiments, the cyclic silicone is of low viscosity. In someembodiments, the cyclic silicone is volatile. In one embodiment, thecyclic silicone is cyclomethicone.

In some embodiments, the foamable compositions described herein are freeof linear (i.e., non-branched) silicones. In some embodiments, thefoamable compositions described herein are free of hydrophilic silicones(i.e., containing hydrophilic or polar groups (e.g., dimethiconol). Inother embodiments the foamable compositions include hydrophilicsilicones, such as dimethiconol, which with glycerol monostearate andoil produced high quality foam.

Further, and again without wishing to be bound by a particular theory,the oil-based foams are believed to be stabilized by the presence of acyclic volatile silicone in the foamable composition. The cyclicvolatile silicone is present in the composition in combination with ahigh concentration of liquid oil (e.g., greater than about 60%) and astabilizing agent. In an embodiment the volatile silicone iscyclomethicone. In some embodiments, the volatile cyclic silicone isused in combination with another silicone. In certain embodiments thesecond silicone is a cyclic silicone. For example, when cyclomethiconewas used in combination with cyclohexasiloxane it produce a foam ofquality. In further embodiments, the volatile silicone is cyclic. Infurther embodiments, the volatile silicone is non cyclic provided itprovides steric or repulsive hinderance by having branched or polargroups.

In addition, without wishing to be bound by a particular theory, theoil-based foams are believed to be stabilized by the presence of a lowviscosity silicone in the foamable composition. The low viscositysilicone is present in the composition in combination with a highconcentration of liquid oil (e.g., greater than about 60%) and astabilizing agent. In some embodiments, the low viscosity silicone isvolatile. In further embodiments, the low viscosity silicone is cyclic.In an embodiment the lower viscosity silicone is cyclomethicone.

As shown in the Examples, using long, straight-chain dimethicone insteadof cyclomethicone in the foamable compositions results in a lowerquality foam. It is believed that dimethicone, which has a hydrophobicchain-like structure, may be located or trapped between the hydrophobicchains of the liquid oil, thereby destabilizing thehydrophobic-hydrophobic interactions between the chains of the oil. Thisdestabilization—without being bound by any theory—is thought to decreasethe formulation viscosity and result in a poorer quality foam, e.g., dueto the quicker draining of the less viscous formulation.

In contrast, cyclomethicone, which has a cyclic structure, has a loweraffinity for the long hydrophobic chains of the liquid oil. Thus, asdescribed above with regard to stearically hindered silicones, it isthought that cyclomethicone does not destabilize the liquid oilstructure and helps to maintain high formulation viscosity, thusproviding improved foam qualities.

Also present in the composition and contributing to the foam stabilityis a surface active agent. In some embodiments, the surface active agentis an ester of a C8-C24 saturated hydrocarbon. In some embodiments, thesurface active agent is a stearic acid derived ester. The surface activeagent is situated at the gas/liquid interface of the foam, lowering thesurface tension at the interface between the gas bubbles and thesurrounding oil phase. This property is beneficial for foam formationand also for the prevention of bubble coalescence, thus furtherstabilizing the foam.

Similarly, the cyclic silicone is located at the gas/liquid interface.Its surface tension assists in stabilizing the foam by lowering surfacetension at the interface. Moreover, with regard to volatile silicones,the volatility is thought to improve the liquid flow at the gas/oilinterface and also enhance the bubble film elasticity. Both of thesefactors contribute to substantially reduce bubble coalescence and foamcollapse.

In one or more embodiments there is provided a substantially waterlessfoamable composition suitable for external or body cavity administrationof an active agent, comprising a foamable carrier and at least oneliquefied or compressed gas propellant wherein the foamable carriercomprises:

about 60% to about 95% by weight of at least one liquid oil;

at least one liquid silicone;

at least one least one foam stabilizing agent;

wherein the foamable composition is substantially a single phase, inwhich the active agent is capable of being dissolved or suspendedsubstantially uniformly;

wherein the foam stabilizing agent is selected from the group consistingof about 0.1% to about 25% by weight of at least one surface-activeagent (which is not primarily a sorbitan ester of a fatty acid) alone orin combination with a foam adjuvant; about 0% to about 5% by weight ofat least one polymeric agent alone or in combination with a foamadjuvant and mixtures of at least one surface-active agent and at leastone polymeric agent with or without a foam adjuvant; andwherein the ratio of the foamable carrier to the propellant is 100:03 to100:35.

A method of making the foamable, single-phase, oil-based compositionsdescribed herein is further provided. As described herein, thecompositions are generally prepared by first combining the liquid oilwith the surface active agent at an elevated temperature, followed bycooling to room temperature. In one embodiment, the components arecombined at a temperature of at least about 50° C., at least about 55°C., at least about 60° C. or at least about 65° C. In anotherembodiment, the components are combined at a temperature between about50° C. to about 65° C.

In one embodiment, the oil/surface active agent combination is cooledrapidly, by exposing the combination to cold temperatures, e.g., lessthan about 40° C., less than about 30° C., less than 25° C., or lessthan about 20° C., or less than about 15° C., or less than about 10° C.,or less than about 5° C., or less than about 0° C. or less than aboutminus 5° C. until it reaches the desired temperature. In one embodiment,rapid cooling is effectuated by placing the combination in an ice bathuntil it reaches the desired temperature. In another embodiment it isplaced in an alcohol water bath. In another embodiment it is placed in awater bath. In a preferred embodiment the cold water bath is blow about20° C. In a preferred embodiment the ice bath is blow about 4° C. In apreferred embodiment the alcohol water bath is blow about minus 5° C.Without wishing to be bound by a particular theory it is thought thatrapid cooling helps to stabilize the formulation by “locking” thehydrophobic ingredients together and stabilizing the oil surfactantstructure. The rate of cooling for the rapid cooling procedure rangesfrom about 2 degrees/minute to about 15 degrees/minute, from about 4degrees/minute to about 15 degrees/minute or 4 degrees/minute to about 8degrees/minute. In some embodiments, the rate of cooling is greater thanabout 2 degrees/minute, about 3 degrees/minute, about 4 degrees/minute,about 5 degrees/minute, about 10 degrees/minute, or about 15degrees/minute. In an alternative embodiment, the oil/surface activeagent combination is cooled slowly. In one embodiment, slow cooling isperformed by keeping the mixture at room temperature until it reachesthe desired temperature.

In another embodiment, the oil/surface active agent combination iscooled slowly. In one embodiment, rapid cooling is effectuated byholding the combination at room temperature until it reaches the desiredtemperature. The rate of cooling for the slow cooling procedure rangesfrom less than about 3 degrees/minute to less than about 0.4degrees/minute, or from less than about 2 degrees/minute to less thanabout 1 degrees/minute. In some embodiments, the rate of cooling is lessthan about 5 degrees/minute, about 4 degrees/minute, about 3degrees/minute, about 2 degrees/minute, or about 1 degrees/minute.

In formulations containing silicone, the silicone is added prior tocooling, during cooling, or at the end of the cooling step (when thecombination is at or near its desired temperature). In one embodiment,the silicone is added after the combination has reached roomtemperature. In another embodiment, the silicone is added once thecombination has reached a desired temperature. In another embodiment,the silicone is added when the combination is within 5° C. of thedesired temperature. For example, in some embodiments, the silicone isadded after the combination is cooled to a temperature of not more than45° C., not more than 40° C., not more than 35° C., not more than 30°C., or not more than 25° C. In some embodiments, the silicone is addedafter the combination is cooled to a temperature between about 15° C. toabout 25° C., between about 20° C. to about 25° C., between about 25° C.to about 45° C., between about 40° C. to about 45° C., between about 25°C. to about 35° C., or between about 25° C. to about 30° C. Followingaddition of the silicone, the formulation is further cooled or warmed,to room temperature, either by slow cooling (i.e., exposure to roomtemperature) or by rapid cooling, as described above. In someembodiments, the silicone is added in different portions at differenttemperatures during the process.

In some embodiments, formulations prepared by fast cooling result inimproved foam quality, smaller bubble size, viscosity, and density.

Definitions

All % values are provided on a weight (w/w) basis.

The term “waterless”, as used herein, means that the compositioncontains no or substantially no, free or unassociated or absorbed water.Similarly, “waterless” or “substantially waterless” compositions containat most incidental and trace amounts of water.

The term “unstable active agent” as used herein, means an active agentwhich is oxidized and/or degraded within less than a day, and in somecases, in less than an hour upon exposure to air, light, skin or waterunder ambient conditions.

The identification of a “solvent”, as used herein, is not intended tocharacterize the solubilization capabilities of the solvent for anyspecific active agent or any other component of the foamablecomposition. Rather, such information is provided to aid in theidentification of materials suitable for use as a part in the foamablecompositions described herein.

The pharmaceutical carriers and compositions described herein aresuitable for dermal or external application of an stable or unstableactive agent. Typically, unstable agents break down upon exposure toair, water vapor or upon contact with the skin. The hydrophobic,oil-based carriers described herein provide stable formulations ofunstable agents, which are active in situ and, and are stable over atime period of at least 1-5 minutes after application. The carriers andcompositions are substantially non-aqueous, and provide not only asoothing effect to the skin, but also provide a therapeutic local and/orsystemic effect from the active agent.

In one or more embodiments the composition comprises a pharmaceutical orcosmetic active agent. In certain embodiments, the active agent isunstable in the presence of water, and in such cases the presence ofwater in the composition is clearly not desirable.

The active agent may be insoluble or fully or partially soluble in thecomposition and to the extent it is insoluble it may be provided in asubstantially homogenous insoluble suspension.

The at least one liquid oil may be selected from a mineral oil avegetable oil, a MCT oil, an essential oil and organic oil, ahydrogenated castor oil and lipids and mixtures thereof.

The liquid oil may further contain an emollient or a hydrophobicsolvent. In some embodiments the liquid oil may contain a solid oil orwax.

In an embodiment there is provided a waterless foamable pharmaceuticalcomposition, wherein said at least one liquid oil is a mineral oil.

In an embodiment there is provided a waterless foamable pharmaceuticalcomposition, wherein the liquid silicone is unmodified.

In an embodiment there is provided a waterless foamable pharmaceuticalcomposition, wherein said oil is selected from mineral oil, hydrogenatedcastor oil and MCT oil.

In an embodiment there is provided a waterless foamable pharmaceuticalcomposition, wherein the emollient is selected from isopropyl myristate,PPG-15 stearyl ether, octyldodecanol, Isohexadecanol, diisopropyladipate, and Cetearyl Octanoate.

Some compositions comprise at least one hydrophobic solvent selectedfrom the group consisting of mineral oil, isopropyl palmitate, isopropylisostearate, diisopropyl adipate, diisopropyl dimerate, maleated soybeanoil, octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopherylacetate, acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone,glyceryl oleate, tocopheryl linoleate, wheat germ glycerides, arachidylpropionate, myristyl lactate, decyl oleate, ricinoleate, isopropyllanolate, pentaerythrityl tetrastearate, neopentylglycoldicaprylate/dicaprate, isononyl isononanoate, isotridecyl isononanoate,myristyl myristate, triisocetyl citrate, octyl dodecanol, unsaturated orpolyunsaturated oils, such as olive oil, corn oil, soybean oil, canolaoil, cottonseed oil, coconut oil, sesame oil, sunflower oil, borage seedoil, syzigium aromaticum oil, hempseed oil, herring oil, cod-liver oil,salmon oil, flaxseed oil, wheat germ oil, evening primrose oils; andessential oils.

The foamable carrier may further including a foam adjuvant selected fromthe group consisting of a fatty alcohol, a fatty acid and a hydroxylfatty acid.

In one or more embodiments the liquid oil is substantially free ofparticles. In a preferred embodiment the liquid oil is free of particlesas determined by normal microscopic examination. In other words thefoamable carrier prior to addition of active agent is substantially asingle phase, and preferably a single phase. In one or more embodimentsthe foamable composition after addition of active agent is substantiallya single phase, preferably a single phase. In yet other embodiments thefoamable composition after addition of active agent is substantially ahomogenous suspension of active agent.

Preferably, the pharmaceutical composition has the following property: afoam quality of at least good up to excellent; and at least one otherproperty selected from: specific gravity in the range of about 0.05gr/mL to about 0.20 gr/mL; a foam texture of a very fine creamy foamconsistency to a fine bubble structure consistency; a sustainability ofmore than 95% for at least one minute upon release thereof to a surfacefrom an aerosol can; capable of withstanding at least one freeze thawcycle without substantial change; having a mean bubble size of less thanabout 200 micron; and compatibility with the at least one active agent.

In some cases, the foamable pharmaceutical composition has at least fourof the properties. In some other cases, the composition has all of theproperties.

The target site for the composition includes the skin, a body cavity, amucosal surface, the nose, the mouth, the eye, the ear canal, therespiratory system, the vagina and the rectum.

In one or more embodiment, the foregoing formulations including anliquid oil are used with a tetracycline antibiotic such as doxycyclineor minocycline for the treatment of acne. The use of an oil-basedformulation for the treatment of acne runs counter to conventionalapproach, which avoid oily bases as exacerbating the underlying acnecondition. In contrast, the current formulations moisturize and protectthe skin. Initial investigations indicate that waterless hydrophobicpreparations have a good “skin feel,” are quickly absorbed and are nottacky.

The present invention relates to a foamable pharmaceutical carriersuitable for external administration of an active agent. In someembodiments, the active agent is unstable, particularly water unstable.

Silicone

A “Silicone” is a largely inert compound with a wide variety of formsand uses. Silicones (more accurately called polymerized siloxanes orpolysiloxanes) are inorganic-organic polymers with the chemical formula[R₂SiO]_(n), where R=organic groups such as (C₁-C₆)-alkyl or(C₁-C₈)-aryl groups (e.g., methyl, ethyl, propyl, and phenyl). Thesematerials consist of an inorganic silicone-oxygen backbone ( . . .—Si—O—Si—O—Si—O— . . . ) with organic side groups (side chains) attachedto the silicone atoms, which are four-coordinate. In some cases organicside groups can be used to link two or more of these —Si—O— backbonestogether. By varying the —Si—O— chain lengths, side groups, andcrosslinking, silicones can be synthesized with a wide variety ofproperties and compositions. Their excellent biocompatibility is partlydue to the low chemical reactivity displayed by silicones, their lowsurface energy and their hydrophobicity.

Silicones such as dimethicone, simethicone and simethicone emulsion havefound wide application in the manufacture of pharmaceuticals due totheir efficient antifoam properties. Dimethicones and simethicones areused as antifoams in anti-flatulent or anti-acid formulations. Siliconesin these products help to suppress the formation of foam in the stomachwithout modifying the gastric pH. This is not surprising as silicones,with their low surface tension (and in particular when compounded withsilicon dioxide) are known to destroy foams in many applications, e.g.in petrol, paper pulp or food processing. This makes themcontraindicated for use in foamable carriers and compositions andespecially in waterless or substantially waterless carriers,compositions and foams. The current application has identified siliconesthat surprisingly produce stable, fine bubble foams using having a highoil content.

Silicone compounds useful in the compositions described herein areselected for their ability to form a stable, waterless or substantiallywaterless, single phase foamable composition. Factors to consider inselecting the appropriate silicone compound include the shape and sizeof the compound, the hydrophilicity or polarity of the compound,viscosity, volatility, surface tension, and interactions with the oiland stabilizing agent (e.g., surface active agent) also present in thecomposition.

With regard to shape and size, as described previously, silicones thatdo not inhibit the hydrophobic-hydrophobic interactions of the oil arethought to produce more stable foams. Exemplary silicones of appropriatesize and shape include, without limitation, cyclic silicones, such asthose having 3 to 6, or 3 to 4 or 3 to 5, (or any of 3, 4, 5, or 6) Si—Ogroups in the cyclic backbone chain (e.g., siloxanes). In someembodiments, the cyclic silicone is a volatile silicone. In someembodiments, the cyclic silicone is a low viscosity silicone. Exemplarycyclic silicones include, without limitation, cyclomethicone,cyclotetrasiloxane, cyclopentasiloxane (e.g., Cyclomethicone 5-NF),cyclohexasiloxane and a mixture of cyclohexasiloxane andcyclopenasiloxane (e.g., DOW CORNING 246 Fluid (d6+d5)). Othernon-limiting examples of silicones of appropriate size and shape aresilicones having side groups or side chains. In some embodiments, theside groups are hydrophobic. In some embodiments, the side groups arestraight chained, while in other embodiments the side groups arebranched. Exemplary side chains include those having 1 to 6, or 2 to 6,or 3 to 6 or 3 to 6 or 5 to 6 carbons or heteroatoms (e.g., O, S, or N)(or any combination thereof). Exemplary linear side chains include,without limitation, methyl, ethyl, propyl, butyl, pentyl, and hexyl.Exemplary branched side chains include, without limitation, isopropyl,isobutyl, and tert-butyl. In one nonlimiting embodiment, the branchedside chain is —O—Si(CH₃)₃. Nonlimiting examples of silicones havingbranched side chains are stearyl dimethicone and phenyltrimethicone,cetyl dimethicone, caprylyl methicone, PEG/PPG 18/18 dimethicone thestructures of which are as follows:

In further embodiments, the side chains are cyclic. Cyclic side chainsinclude aliphatic side chains and aromatic side chains. A nonlimitingexample of a cyclic side chain is phenyl.

With regard to silicones having hydrophilic or polar groups, asdescribed previously, silicones that are repulsive with regard to thehydrophobic chains of the oil are thought to produce more stable foamsbecause they do not inhibit the hydrophobic-hydrophobic interactions ofthe oil. Exemplary hydrophilic or polar groups include oxygen-containinggroups, such as carbonyl groups, hydroxy groups, ether, ester,carboxylic groups, which replace one or more methyl groups. Thehydrophilic/polar groups are present alternatively in the main chain ofthe silicone or in a side chain. Nonlimiting examples of a siliconehaving a hydrophilic group are PEG/PPG 18/18 dimethicone anddimethiconol, the structures of which are:

Another type of specific non limiting volatile silicone in accordancewith the present invention is a volatile short chain linearalkylmethylsilicone fluid. The volatile short chain linearalkylmethylsilicone fluid has the formula:

In the above formula, the integer represented by n has a value of fiveto twelve. Preferably, n has a value of five to eight. Compounds mostpreferred in terms of this invention are3-hexyl-1,1,1,3,5,5,5,-heptamethyltrisiloxane and3-octyl-1,1,1,3,5,5,5-heptamethyltrisiloxane. Measured at twenty-fivedegrees Centigrade, these two preferred compounds have a viscosity oftwo Centistokes and five Centistokes, respectively.

Yet another type of volatile silicone in accordance with the presentinvention is a volatile short chain linear phenylmethylsilicone fluid.The volatile short chain linear phenylmethylsilicone fluid has theformulan:

This compound is 3-phenyl-1,1,1,3,4,4,4-heptamethyltrisiloxane.

Further volatile silicone fluids useful in the compositions describedherein include, without limitation, are decamethylcyclopentasiloxane(DMCPS) which has a molecular weight of about 370, a refractive index of1.40, and the formula [(Me ₂)SiO]₅; the compound3-hexyl-1,1,1,3,5,5,5-heptamethyltrisiloxane (HHMTS) which has amolecular weight of about 306, and a refractive index of 1.41; and thecompound 3-phenyl-1,1,1,3,5,5,5-heptamethyltrisiloxane (PHMTS) which hasa molecular weight of about 298 and a refractive index of 1.45. Thesecompounds will be referred to in the examples and in the table below asDMCPS, HHMTS, and PHMTS, respectively, for the sake of convenience.

In an embodiment, the silicone component(s) is selected for particularvolatility properties. In one embodiment the silicone is a liquidvolatile silicone. By volatile is meant that the silicone or at leastpart will pass into vapour if left in an open container at normal levelsof temperature and pressure. In some embodiments, the volatile siliconeis a cyclic silicone. In some embodiments, the volatile silicone is asiloxane having 3 to 6, or 4 or 5, Si—O groups in the cyclic backbonechain. In some embodiments, the volatile silicone is a low viscositysilicone.

With regard to viscosity and volatility, silicones that have lowerviscosity are generally considered to be more volatile. Accordingly, insome embodiments, the silicone is a low viscosity silicone. In anembodiment, a liquid silicone is a low viscosity liquid silicone.Suitable volatile silicone fluids may be cyclic or linear. For example,volatile silicones include, without limitation, silicones having aviscosity of less than about 10, less than about 8, less than about 6,or less than about 5 centistokes at 25° C. In an embodiment theviscosity is between about 10 to about 0.5 cps. In certain embodimentsthe viscosity is less than about 5 cps. Linear volatile siliconesgenerally have viscosities of less than about five centistokes at 25°C., whereas the cyclic silicones have viscosities of less than about 10centistokes. Volatile dimethicones are fluids with viscosities of 0.65to 2 mm²/s of 5.0 mm²/s. A comparison of the viscosity of a volatilesilicone, cyclomethicone, with a nonvolatile silicone, dimethicone, isshown in Table 1.

TABLE 1 INCI SCIENTIFIC NAME CAS No. NAME VISCOSITY Dimethicone9006-65-9 polydimethyl- 350 CPS siloxane med. weight Cyclomethicone541-02-06 decamethylcyclo- 4 CPS pentasiloxane (v. light) * to figureCPS by comparison: H₂O (water) has a viscosity of 1-5 CPS.

Accordingly, in some embodiments, the silicone is a volatile siliconeincluding, but not limited to (i) a volatile short chain linear siliconefluid having in its molecule only methyl groups, (ii) a volatile cyclicsilicone fluid having in its molecule only methyl groups, (iii) avolatile short chain linear silicone fluid having in its molecule bothmethyl groups and phenyl groups, or (iv) a volatile short chain linearsilicone fluid having in its molecule both methyl groups and alkylgroups containing up to twelve carbon atoms, but preferably six, seven,or eight carbon atoms. All of these fluids have a vapor pressure whichis less than 0.10 mm Hg, measured at twenty degrees Centigrade and 760mm pressure.

One type of volatile silicone in accordance with the present inventionis a low viscosity methylsilicone fluid. The volatile low viscositymethylsilicone fluid corresponds to the average unit formula (CH ₃)_(a)SiO_((4-a/2)) wherein a is an integer having an average value of fromtwo to three. For example, representative compounds arecyclopolysiloxane compounds of the general formula [(CH ₃)₂ SiO]_(x),and linear siloxane compounds of the general formula (CH ₃)₃ SiO[(CH₃)₂SiO]_(y) Si(CH ₃)₃, in which x is an integer having a value of fromthree to ten, and y is an integer having a value of from zero to aboutfour.

In some embodiments, the volatile low viscosity methylsilicone fluidcontains dimethylsiloxane units and optionally trimethylsiloxane units.In some embodiments, the methylsilicone fluid has a viscosity of lessthan about ten centistokes.

In some embodiments, the volatile low viscosity methylsilicones haveboiling points generally less than about two hundred-fifty degreesCentigrade, and possess viscosities preferably generally less than aboutten centistokes measured at twenty-five degrees Centigrade. In someembodiments, the viscosity is 0.65 to 5.0 centistokes. Cyclomethiconehas a vapor pressure of 0.015 kPa at 25 C. The cyclopolysiloxanecompounds have been assigned the adopted name “CYCLOMETHICONE” by TheCosmetics, Toiletries and Fragrance Association, Inc., Washington, D.C.(CTFA). Both the cyclopolysiloxanes and the linear siloxanes are clearfluids, and are essentially odorless, nontoxic, nongreasy andnonstinging. Cosmetically, these methylsilicone fluids are nonirritatingto skin and nail surfaces, and exhibit enhanced spreadability and easeof rub-out when applied. Once applied, the materials evaporate leavingbehind no residue.

Methylsilicone fluids which are operable in accordance with the presentinvention leave substantially no residue after thirty minutes at roomtemperature when one gram of fluid is placed at the center of a No. 1circular filter paper having a diameter of 185 mm supported at itsperimeter in open room atmosphere. By methylsilicone fluid is meant acomposition containing two or more silicon atoms, all of which arebonded by way of at least one oxygen atom to at least one other siliconatom and at least one methyl radical, each silicon valence not satisfiedby oxygen being satisfied by a methyl radical. In some embodiments,methylsilicone fluids include, without limitation, hexamethyldisiloxanewhich has a boiling point of 99.5 degrees Centigrade and the formula Me₃ SiOSiMe ₃; octamethyltrisiloxane which has a boiling point of 152degrees Centigrade and the formula Me ₃ SiOMe ₂ SiOSiMe ₃;hexamethylcyclotrisiloxane which has a boiling point of 133 degreesCentigrade and the formula [(Me ₂)SiO] ₃; octamethylcyclotetrasiloxanewhich has a boiling point of 171 degrees Centigrade and the formula [(Me₂)SiO] ₄; and decamethylcyclopentasiloxane which has a boiling point of205 degrees Centigrade and the formula [(Me ₂)SiO] ₅.

These methylsilicone fluids may be used alone, or as mixtures incombinations of two or more. Mixtures of the methylsilicone fluids willresult in a volatile material having an evaporating behavior differentfrom any one of the individual methylsilicone fluids.

The methylsilicone fluids and methods for their preparation are known inthe art.

In addition, with regard to surface tension, silicones that have lowsurface tension are thought to contribute to the stability of the foamsdescribed herein. Similarly, with regard to interaction with the oil andstabilizing agent, silicones that can interact with these components toproduce a more stable foam are desired.

In certain embodiments cyclomethicone is used in combination with othersilicones. In some embodiments, a combination of silicones havingdifferent sizes and shapes, hydrophilicity, polarity, or volatility isselected. For example, in some embodiments, the volatile silicone is acombination of volatile, non-volatile, or partially non-volatilesilicones, such that the viscosity of the combination is that is that ofa volatile silicone. In certain embodiments, the foamable formulationincludes at least a volatile element including at least one volatile orpartially volatile silicone and a non-volatile element including atleast one non-volatile oil and optionally a non-volatile silicone. Uponapplication to a surface, one or all of the silicones of the volatileelement evaporates and the non-volatile element remains at the site ofapplication.

A description of various volatile silicone oils is found in Todd, etal., “Volatile Silicone Fluids for Cosmetics”, 91 Cosmetics andToiletries, 27-32 (1976), incorporated by

In some embodiments, the silicone is a low viscosity silicone. Forexample, in some embodiments, the silicone has a viscosity of less thanabout 10 centistokes at 25° C.

In some embodiments, the silicone is not a dimethicone.

In one embodiment the silicone is an unmodified silicone (i.e., notsynthetically modified). Unmodified silicones stay on or near thesurface of the skin. Not only are the molecules too big to physicallyenter past the upper living cells—they associate with the upper layer ofdrying skin—but they also cannot penetrate cell membranes due to theirlarge size. They also dislike both the water and proteins inside cells.Silicones may be used in the foam compositions for topical and bodycavity compositions. They evaporate after helping to carry oils into thetop layer of epidermis. From there, they may be absorbed by the skin.

Lower molecular weight siloxanes are frequently used due theirvolatility and generally dry skin feel. The can be important in tryingto overcome the particularly dry skin feeling associated with waterlessfoam compositions. These can include linear as well as cyclic siloxanes.A low molecular weight linear material is hexamethyldisiloxane,(Me)₃SiOSi(Me)₃ (HMDS), which is said to have a viscosity of about 0.48mPa·s.

Inhalation of aerosols of oily or fatty-type materials, includingsilicones, into alveolar regions of the lung may result in physicaldisturbances of the lining of the lung with associated effects. Thismakes the selection of foams as a method of application of siliconecontaining substances desirable since it should avoid the risk ofinhalation when compared to aerosol sprays.

Polysiloxanes have generally poor compatibility with oils, such that thecompatibility (solubility) of the polysiloxanes with the oils decreasesas the number of dimethylsiloxy units increases. Thus, it is far fromstraight forward to discover waterless and substantially waterlesssilicone carriers, compositions and foams which also contain hydrophobicsolvents like oils or which also comprise other fatty or greasysubstances. Nevertheless successful formulations producing a foam ofquality can be achieved with polysiloxanes.

In an embodiment wax silicone or solid silicone is used in combinationwith liquid silicone. An example is stearyloxytrimethylsilane,CH₃(CH₂)₁₇OSiMe₃. The wax silicone will dissolve in the oil carrier andpropellant.

Liquid Oil

In some embodiments, the liquid oil is a mineral oil. The mineral oilmay be heavy or light or a combination thereof. Exemplary liquid oilsalso include, without limitation, one or more of a vegetable oil, MCToil (i.e., medium chain triglycerides, such as caproic (C6), caprylic(C8), capric (C10) and lauric acid (C12)), an essential oil, an organicoil or a lipid. MCT oil may be obtained as a mixture of capric/caprylictriglycerides. In some embodiments, the liquid oil consists essentiallyof a mineral oil. In some embodiments, the liquid oil consists of amineral oil. In an embodiment the liquid oil is essentially a mineraloil. In another embodiment it may comprise a majority of mineral oilcombined with one or more other oils. In one or more embodiments theliquid oil may further comprise an emollient. In one or more embodimentsthe liquid oil may further comprise a hydrophobic solvent. In one ormore embodiments the liquid oil may further comprise a polypropyleneglycol (PPG) alkyl ether such as a PPG stearyl ether for example PPG-15.

In some embodiments, the liquid oil is one or more of mineral oil, MCToil, liquid paraffin, vegetable oil, essential oil, organic oil, andlipids.

Polypropylene Glycol (PPG) Alkyl Ethers

In the context, a polypropylene glycol alkyl ether (PPG alkyl ether) isa liquid, water-insoluble propoxylated fatty alcohol, having themolecular formula of RO(CH₂CHOCH₃)_(n); wherein “R” is astraight-chained or branched C₄ to C₂₂ alkyl group; and “n” is in therange between 4 and about 50.

(PPG alkyl ethers), are organic liquids that function asskin-conditioning agent in pharmaceutical and cosmetic formulations.They possess exceptional emollient effect, side by side with enhancedsolvency properties, which facilitates solubilization of active agentsin a composition comprising a PPG alkyl ether. PPG alkyl ethers offerthe following advantages when used as a component in the foamablecomposition:

-   -   Due to the polypropylene glycol moiety, PPG alkyl ethers possess        certain surface active properties and they assist in the        coupling of polar and non-polar oils in an emulsion formulation;    -   PPG alkyl ethers are non-occlusive; offering a long-lasting and        velvety feel;    -   They are chemically stable at extreme pH conditions;    -   Excellent solvency properties, particularly with difficult to        formulate active agents; and    -   When combined with certain surfactants, such as Brij 72 and Brij        721, PPG alkyl ethers form oleosomes and/or liquid crystal        structures, which provide long lasting moisturization, excellent        spreading as well as prolonged hydration properties.

Exemplary PPG alkyl ethers include PPG-2 butyl ether, PPG-4 butyl ether,PPG-5 butyl ether, PPG-9 butyl ether, PPG-12 butyl ether, PPG-14 butylether, PPG-15 butyl ether, PPG-16 butyl ether, PPG-17 butyl ether,PPG-18 butyl ether, PPG-20 butyl ether, PPG-22 butyl ether, PPG-24 butylether, PPG-26 butyl ether, PPG-30 butyl ether, PPG-33 butyl ether,PPG-40 butyl ether, PPG-52 butyl ether, PPG-53 butyl ether, PPG-10 cetylether, PPG-28 cetyl ether, PPG-30 cetyl ether, PPG-50 cetyl ether,PPG-30 isocetyl ether, PPG-4 lauryl ether, PPG-7 lauryl ether, PPG-2methyl ether, PPG-3 methyl ether, PPG-3 myristyl ether, PPG-4 myristylether, PPG-10 oleyl ether, PPG-20 oleyl ether, PPG-23 oleyl ether,PPG-30 oleyl ether, PPG-37 oleyl ether, PPG-50 oleyl ether, PPG-11stearyl ether. Preferred PPG alkyl ethers according to the presentinvention include PPG-15 stearyl ether (also known as Earlamol E®,Unichema), PPG-2 butyl ether, PPG-9-13 butyl ether and PPG-40 butylether. PPG alkyl ethers can be incorporated in the foamable composition.

PPG Stearyl Ethers

PPG stearyl ethers function as skin-conditioning and penetration agentsin cosmetic formulations.

Polypropylene glycol stearyl ether 15, also known as polyoxypropylene 15stearyl ether or as “PPG-15”, and having a CAS Registry No. of[25231-21-4], is a stearyl ether having about 15 propylene oxide unitsincorporated in its structure. PPG-15 stearyl ether is a clear liquid,soluble in mineral oil, isopropyl ethers, cottonseed oil, ethanol,isopropanol and hexadecyl alcohol, to name a few, and is particularlyuseful as a solvent of difficult to formulate ingredients, such assunscreens, aluminum chlorhydrate salts and skin toners. It is insolublein water, propylene glycol and glycerin. PPG-15 stearyl ether is aninert and highly stable compound.

PPG stearyl ether also functions as a coupling agent, allowing, forexample, the compatibility of polar and non-polar oils with ethanol andperfumes in after shave lotions. It is chemically stable at extreme pHlevels and at the same time saturated, providing excellent shelf lifestability.

Polymeric Agent

In some embodiments, the composition contains a polymeric agent. Thepresence of a polymeric agent promotes the creation of a foam havingfine bubble structure, which does not readily collapse upon release fromthe pressurized aerosol can. The polymeric agent serves to stabilize thefoam composition and to control drug residence in the target organ.Preferably, the polymeric agent is soluble or readily dispersible in thepolyol; or in the mixture of a polyol and an additional solvent.

Non-limiting examples of polymeric agents that are soluble or readilydispersible in propylene glycol are Hydroxypropylcellulose and carbomer(homopolymer of acrylic acid is crosslinked with an allyl etherpentaerythritol, an allyl ether of sucrose, or an allyl ether ofpropylene, such as Carbopol® 934, Carbopol® 940, Carbopol® 941,Carbopol® 980 and Carbopol® 981.

Other polymeric agents are suitable for use according to the presentinvention provided that they are soluble or readily dispersible in thepolyol; or in the mixture of a polyol and an additional solvent, on acase by case basis.

Exemplary polymeric agents include, in a non-limiting manner,naturally-occurring polymeric materials, such as locust bean gum, sodiumalginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum,sodium alginate, xanthan gum, quince seed extract, tragacanth gum, guargum, cationic guars, hydroxypropyl guar gum, starch, amine-bearingpolymers such as chitosan; acidic polymers obtainable from naturalsources, such as alginic acid and hyaluronic acid; chemically modifiedstarches and the like, carboxyvinyl polymers, polyvinylpyrrolidone,polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acidpolymers, polyvinyl acetate polymers, polyvinyl chloride polymers,polyvinylidene chloride polymers and the like.

Additional exemplary polymeric agents include semi-synthetic polymericmaterials such as cellulose ethers, such as methylcellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxy propylmethyl cellulose, methylhydroxyethylcellulose,methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose,carboxymethyl cellulose, carboxymethylcellulosecarboxymethylhydroxyethylcellulose, and cationic celluloses.Polyethylene glycol, having molecular weight of 1000 or more (e.g., PEG1,000, PEG 4,000, PEG 6,000 and PEG 10,000) also have gelling capacityand while they are considered herein as “secondary solvents”, asdetailed herein, they are also considered polymeric agents.

Mixtures of the above polymeric agents are contemplated.

The concentration of the polymeric agent should be selected so that thecomposition, after filling into aerosol canisters, is flowable, and canbe shaken in the canister. In one or more embodiments, the concentrationof the polymeric agent is selected such that the viscosity of thecomposition, prior to filling of the composition into aerosol canisters,is less than 13,000 CPs, and more preferably, less than 10,000 CPs.

Surface-Active Agents

In the various embodiments, the compositions described herein comprise asurface-active agent. Surface-active agents (also termed “surfactants”)include any agent linking oil and water in the composition, in the formof emulsion. A surfactant's hydrophilic/lipophilic balance (HLB)describes the emulsifier's affinity toward water or oil. HLB is definedfor non-ionic surfactants. The HLB scale ranges from 1 (totallylipophilic) to 20 (totally hydrophilic), with 10 representing an equalbalance of both characteristics. Lipophilic emulsifiers formwater-in-oil (w/o) emulsions; hydrophilic surfactants form oil-in-water(o/w) emulsions. The HLB of a blend of two emulsifiers equals the weightfraction of emulsifier A times its HLB value plus the weight fraction ofemulsifier B times its HLB value (weighted average). In many cases asingle surfactant may suffice. In other cases a combination of two ormore surfactants is desired. Reference to a surfactant in thespecification can also apply to a combination of surfactants or asurfactant system. As will be appreciated by a person skilled in the artwhich surfactant or surfactant system is more appropriate is related tothe vehicle and intended purpose. In general terms a combination ofsurfactants can be significant in producing breakable forms of goodquality. It has been further discovered that the generally thoughtconsiderations for HLB values for selecting a surfactant or surfactantcombination are not always binding for emulsions and moreover forsubstantially non-aqueous carriers the usual guidelines are lessapplicable. For oil based waterless systems HLB values may have littlesignificance other than to indicate the proportion of an amphiphilicmolecule that is hydrophobic and therefore potentially more at home inan oil single phase environment. Surfactants can play a significant rolein foam formation where the foamable formulation is a single phasecomposition.

In selecting a suitable surfactant or surfactant combination for use inthe substantially single phase formulations described herein selectionrelates to a multiple of factors including but not limited to solubilityand miscibility in the liquid oil and in the silicone to producesubstantially a single phase; the ability to form foam of quality; theability to stabilize the extruded foam; a HLB value which preferablysuggests potential compatibility with the liquid oil and the silicone;and solubility of surfactant in the formulation.

In certain embodiments the surfactant can have thickening properties. Incertain embodiments the surfactant can effect the viscosity of the prefoam formulation (PFF). In certain other embodiments the surfactant haslittle or no effect. The concentration of the surfactant agent incombination with the oil and silicone and other ingredients should beselected so that the composition, after filling into aerosol canisters,is flowable, and can be shaken in the canister. In one or moreembodiments, the concentration of the surfactant agent is selected suchthat the viscosity of the composition, prior to filling of thecomposition into aerosol canisters, is less than 13,000 CPs, and morepreferably, less than 10,000 CPs, preferably below about 9000, morepreferably below about 6000 cps; In one or more embodiments averagebubble size of the resultant foam should be below about 200 microns,preferably below 150 and more preferably below 100 microns; In one ormore embodiments foam density is below about 0.2 preferably below about0.1 g/ml. In one or more embodiments hardness of the resultant foam isin the range of about 5 to about 35.

According to one or more embodiments the composition contains a singlesurface active agent having an HLB value between about 2 and 9, or morethan one surface active agent and the weighted average of their HLBvalues is between about 2 and about 9.

According to one or more embodiments the composition contains a singlesurface active agent having an HLB value between about 7 and 14,(preferably about 7 to about 12) or more than one surface active agentand the weighted average of their HLB values is between about 7 andabout 14 (preferably about 7 to about 12).

According to one or more other embodiments the composition contains asingle surface active agent having an HLB value between about 9 andabout 19, or more than one surface active agent and the weighted averageof their HLB values is between about 9 and about 19.

In a waterless or substantially waterless environment a wide range ofHLB values may be suitable. In one or more embodiments the HLB may notplay a role in a single phase system

Preferably, the composition contains a non-ionic surfactant. Nonlimitingexamples of possible non-ionic surfactants include a polysorbate,polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20)sorbitan monooleate, a polyoxyethylene fatty acid ester, polyoxyethylene(8) stearate (Myrj 45), polyoxyethylene (20) stearate (Myrj 49),polyoxyethylene (40) stearate (Myrj 52 ) and polyoxyethylene (100)stearate (Myrj 59); a polyoxyethylene alkyl ether, polyoxyethylene cetylether, steareths such as steareth 2, Steareth 21 (Brij 721),polyoxyethylene (23) cetyl ether (Brij38), polyoxyethylene (2) cetylether (Brij 52), polyoxyethylene (10) cetyl ether (Brij 56 ) a sucroseester, a partial ester of sorbitol and its anhydrides, sorbitanmonolaurate, sorbitan monolaurate, a monoglyceride, a fatty acid esterof glycerol, a diglyceride, isoceteth-20 , a mono-ester of sucrose withfatty acids, a di-ester of sucrose with fatty acids, and a tri-ester ofsucrose with fatty acids. In certain embodiments, suitable sucroseesters include those having high monoester content, which have higherHLB values. However, sorbitan esters are not used alone as primarysurfactants. In an embodiment if present sorbitan esters are used incombination with one or more primary surfactants and functions as asecondary or co-surfactant.

In one or more embodiments the surfactant is selected to produce a foamof quality being of least of about good quality foam and preferably ofexcellent quality foam. In one or more embodiments the surfactantincludes, a fatty acid ester of glycerol, such as a mono, di or trifatty ester of stearic acid or palmitic acid or arachidic acid orbehenic acid. In one or more embodiments the surfactant is used on itsown with the oil. In certain other embodiments the surfactant is used incombination with one or more other surfactants, such as, those listedbelow. In an embodiment the combination is, for example, glycerolmonostearate, glycerol palmitostearate, and PEG 100 stearate. Othersimilar combinations are readily envisaged.

TABLE 2 Glycerol fatty acid esters Fatty acid Ester Function Solubility(main) Comments glyceryl Thickener, Practically Beheneic (C22) Nottested behenate lubricant insoluble in oil and water glyceryl Non ionicSoluble in oil Oleic (double Fairly Good monooleate Sufactant andpractically bond in side Foam with insoluble in chain (C18) mineral oiland water silicone glyceryl Non ionic Soluble in Stearic (C18)Good-Excellent Foam monostearate emulsifying mineral oil and withmineral oil (GMS) agent practically and silicone oil insoluble in eventhough GMS and water other fatty acid monoesters are not efficientemulsifiers. glyceryl Sustained Practically Mixture of mono Excellentfoam palmitostearate release, insoluble in (~<17%), di, and with mineraloil lubricant mineral oil and triglycerides of and silicone water C16and C18 fatty acids

In an embodiment the surfactant is an ether for example polyoxyethylene(26) glycerol ether.

In certain embodiments, surfactants are selected which can provide aclose packed surfactant layer. To achieve such objectives combinationsof at least two surfactants are selected. Preferably, they should becomplex emulgators and more preferably they should both be of a similarmolecular type; for example, a pair of ethers, like steareth 2 andsteareth 21, or a pair of esters, for example, PEG-40 stearate andpolysorbate 80. Ideally, the surfactants can be ethers. In certaincircumstances POE esters cannot be used and a combination of sorbitanlaurate and sorbitan stearate or a combination of sucrose stearic acidester mixtures and sodium laurate may be used. All these combinationsdue to their versatility and strength may also be used satisfactorilyand effectively with ether formulations, although the amounts andproportion may be varied according to the formulation and its objectivesas will be appreciated by a man of the art.

It has been discovered also that by using a derivatized hydrophilicpolymer with hydrophobic alkyl moieties as a polymeric emulsifier suchas pemulen it is possible to stabilize the emulsion better about or atthe region of phase reversal tension. Other types of derivatizedpolymers like silicone copolymers, derivatized starch [Aluminum StarchOctenylsuccinate (ASOS)]/[DRY-FLO AF Starch], and derivatized dextrinmay also a similar stabilizing effect.

A series of dextrin derivative surfactants prepared by the reaction ofthe propylene glycol polyglucosides with a hydrophobicoxirane-containing material of the glycidyl ether are highlybiodegradable. [Hong-Rong Wang and Keng-Ming Chen, Colloids and SurfacesA: Physicochemical and Engineering Aspects Volume 281, Issues 1-3, 15Jun. 2006, Pages 190-193].

Non-limiting examples of non-ionic surfactants that have HLB of about 7to about 12 include steareth 2 (HLB˜4.9); glycerol monostearate/PEG 100stearate (Av HLB˜11.2); stearate laureth 4 (HLB˜9.7) and cetomacrogolether (e.g., polyethylene glycol 1000 monoacetyl ether).

Non-limiting examples of surfactants, which have a HLB of 4-19 are setout in the Table below:

Surfactant HLB steareth 2 ~4.9 glycerol monostearate/PEG 100 stearate Av~11.2 glyceryl stearate ~4 steareth-21 ~15.5 peg 40 stearate ~16.9polysorbate 80 ~15 sorbitan stearate ~4.7 laureth 4 ~9.7 sorbitanmonooleate (span 80) ~4.3 ceteareth 20 ~15.7 steareth 20 ~15.3 ceteth 20~15.7 macrogol cetostearyl ether ~15.7 ceteth 2 (Lipocol C-2) ~5.3PEG-30 dipolyhydroxystearate ~5.5 sucrose distearate (Sisterna SP30) ~6polyoxyethylene (100) stearate ~18.8

In some embodiments, the compositions described herein include Sepigel305. Sepigel 305 comprises polyacrylamide and C13-14 isoparaffin andlaureth-7. It acts as a surfactant and as a thickening and emulsifyingagent, and comes in a liquid, very easy to handle form. It requiresneither premixing, nor high rate of shear nor neutralisation. Sepigel305 can be used to emulsify all types of oil phase without heating,producing gel-cream with a rich, silky texture that are easy to applyand rapidly absorbed by the skin.

More exemplary stabilizing surfactants which may be suitable for use inthe present invention are found below.

PEG-Fatty Acid Monoester Surfactants, such as:

Chemical name Product example name HLB PEG-30 stearate Myrj 51 >10PEG-40 laurate Crodet L40 (Croda) 17.9 PEG-40 oleate Crodet O40 (Croda)17.4 PEG-45 stearate Nikkol MYS-45 (Nikko) 18 PEG-50 stearate Myrj53 >10 PEG-100 stearate Myrj 59, Arlacel 165 (ICI) 19

PEG-Fatty Acid Diester Surfactants, such as:

Chemical name Product example name HLB PEG-4 dilaurate Mapeg ™ 200 DL(PPG), 7 Kessco ™ PEG 200 DL (Stepan), LIPOPEG 2-DL (Lipo Chem.) PEG-4distearate Kessco ™ 200 DS 5 (Stepan. sub) PEG-32 dioleate Kessco ™ PEG1540 DO (Stepan) 15 PEG-400 dioleate Cithrol 4DO series (Croda) >10PEG-400 disterate Cithrol 4DS series (Croda) >10 PEG-20 glyceryl oleateTagat ™ O (Goldschmidt) >10

Transesterification Products of Oils and Alcohols, such as:

Chemical name Product example name HLB PEG-30 castor oil Emalex C-30(Nihon Emulsion) 11 PEG-40 hydrogenated Cremophor RH 40 (BASF), 13castor oil Croduret (Croda), Emulgin HRE 40 (Henkel)

Polyglycerized Fatty Acids, such as:

Chemical name Product example name LB Polyglyceryl-6 Caprol ™ 6G20(ABITEC); PGO- 8.5 dioleate 62 (Calgene), PLUROL OLEIQUE CC 497(Gattefosse)Hodag

PEG-Sorbitan Fatty Acid Esters, such as:

Chemical name Product example name HLB PEG-20 sorbitan Tween-20(Atlas/ICI), Crillet 1 17 monolaurate (Croda), DACOL MLS 20 (Condea)PEG-20 sorbitan Tween 40 (Atlas/ICI), Crillet 2 16 Monopalmitate (Croda)PEG-20 sorbitan Tween-60 (Atlas/ICI), Crillet 3 15 monostearate (Croda)PEG-20 sorbitan Tween-80 (Atlas/ICI), Crillet 4 15 monooleate (Croda)

Polyethylene Glycol Alkyl Ethers, such as:

Chemical name Product example name HLB PEG-2 oleyl ether oleth-2 Brij92/93 (Atlas/ICI) 4.9 PEG-3 oleyl ether oleth-3 Volpo 3 (Croda) <10PEG-5 oleyl ether oleth-5 Volpo 5 (Croda) <10 PEG-10 oleyl etheroleth-10 Volpo 10 (Croda), Brij 12 96/97 (Atlas/ICI) PEG-20 oleyl etheroleth-20 Volpo 20 (Croda), Brij 15 98/99 (Atlas/ICI) PEG-4 lauryl etherlaureth-4Brij 30 (Atlas/ICI) 9.7 PEG-23 lauryl ether laureth-23Brij 35(Atlas/ICI) 17 PEG-10 stearyl ether Brij 76 (ICI) 12 PEG-2 cetyl etherBrij 52 (ICI) 5.3

Sugar Ester Surfactants, such as:

Chemical name Product example name HLB Sucrose distearate Sisterna SP50,Surfope 1811 11

Sorbitan Fatty Acid Ester Surfactants, such as Span 40, 60 and 80 havenot been found suitable on their own with the high oil silicone foamableformulations:

Chemical name Product example name HLB Sorbitan monolaurate Span-20(Atlas/ICI), Crill 1 8.6 (Croda), Arlacel 20 (ICI) Sorbitanmonopalmitate Span-40 (Atlas/ICI), Crill 2 6.7 (Croda), Nikkol SP-10(Nikko) Sorbitan monooleate Span-80 (Atlas/ICI), Crill 4 4.3 (Croda),Crill 50 (Croda) Sorbitan monostearate Span-60 (Atlas/ICI), Crill 3 4.7(Croda), Nikkol SS-10 (Nikko)

In one or more embodiments the surface active agent is a complexemulgator in which the combination of two or more surface active agentscan be more effective than a single surfactant and provides a morestable formulation or improved foam quality than a single surfactant.For example and by way of non-limiting explanation it has been foundthat by choosing say two surfactants, one hydrophobic and the otherhydrophilic the combination can produce a more stable emulsion than asingle surfactant. Preferably, the complex emulgator comprises acombination of surfactants wherein there is a difference of about 4 ormore units between the HLB values of the two surfactants or there is asignificant difference in the chemical nature or structure of the two ormore surfactants.

Specific non-limiting examples of surfactant systems are, combinationsof polyoxyethylene alkyl ethers, such as steareth 2 and steareth 20;steareth 2 and steareth 21 (Brij 72/Brij 721); combinations ofpolyoxyethylene stearates such as PEG 40 stearate and PEG 100 stearate(Myrj 52/Myrj 59); combinations of sucrose esters, such as sucrosestearate and sucrose distearate (Surphope 1816/Surphope 1807);combinations of sorbitan esters, such as sorbitan monolaurate andsorbitan monooleate (Span 20/Span 80); sorbitan monolaurate and sorbitanmonostearate (Span 20/Span 60; combinations of sucrose esters andsorbitan esters, such as sucrose distearate and sorbitan monostearate(Surphope 1811 and Span 60); combinations of liquid polysorbatedetergents and PEG compounds, such as PEG-20 sorbitan monooleate andPEG-40 stearate (Tween 80/Myrj 52 ); methyl glucose sesquistearate;polymeric emulsifiers, such as acrylates/C10-30 alkyl acrylatecrosspolymers (Permulen TRI or TR2); liquid crystal systems, such assorbitan stearate and sucrose cocoate (Arlatone 2121), sodium stearylphthalamate (Stepan Mild RM1), polyglyceryl-10 pentastearate and behenylalcohol and sodium stearoyl lactylate (Nikomulese 41) and cetearylalcohol and cetearyl glucoside (Montanov 68) and the like.

In certain embodiments the surfactant is preferably one or more of thefollowing: a combination of steareth-2 and steareth-21 on their own orin combination with glycerol monostearate (GMS); in certain otherembodiments the surfactant is a combination of polysorbate 80 and PEG-40stearate. In certain other embodiments the surfactant is a combinationof glycerol monostearate and PEG 100 stearate. In certain otherembodiments the surfactant is a combination of two or more of stearate21, PEG 40 stearate, and polysorbate 80. In certain other embodimentsthe surfactant is a combination of two or more of laureth 4, sorbitanmonooleate (Span80) and polysorbate 80. In certain other embodiments thesurfactant is a combination of two or more of GMS and a ceteareth. Incertain other embodiments the surfactant is a combination of two or moreof steareth 21, ceteareth 20, ceteth 2 and laureth 4 . In certain otherembodiments the surfactant is a combination of ceteareth 20 andpolysorbate 40 stearate. In certain other embodiments the surfactant isa combination of sorbitan monostearate (Span 60 )and GMS. In certainother embodiments the surfactant is a combination of two or all of PEG40 stearate, sorbitan stearate and polysorbate 60.

In certain other embodiments the surfactant is one or more of sucrosestearic acid esters, sorbitan laureth, and sorbitan stearate.

Without being bound by any particular theory or mode of operation, it isbelieved that the use of non-ionic surfactants with significanthydrophobic and hydrophilic components, increase the emulsifier or foamstabilization characteristics of the composition. Similarly, withoutbeing bound by any particular theory or mode of operation, usingcombinations of surfactants with high and low HLB's to provide arelatively close packed surfactant layer may strengthen the formulation.

In one or more embodiments the stability of the composition can beimproved when a combination of at least one non-ionic surfactant havingHLB of less than 9 and at least one non-ionic surfactant having HLB ofequal or more than 9 is employed. The ratio between the at least onenon-ionic surfactant having HLB of less than 9 and the at least onenon-ionic surfactant having HLB of equal or more than 9, is between 1:8and 8:1, or at a ratio of 4:1 to 1:4. The resultant HLB of such a blendof at least two emulsifiers is preferably between about 9 and about 14.

Thus, in an exemplary embodiment, a combination of at least onenon-ionic surfactant having HLB of less than 9 and at least onenon-ionic surfactant having HLB of equal or more than 9 is employed, ata ratio of between 1:8 and 8:1, or at a ratio of 4:1 to 1:4, wherein theHLB of the combination of emulsifiers is preferably between about 5 andabout 18.

In certain cases, the surface active agent is selected from the group ofcationic, zwitterionic, amphoteric and ampholytic surfactants, such assodium methyl cocoyl taurate, sodium methyl oleoyl taurate, sodiumlauryl sulfate, triethanolamine lauryl sulfate and betaines.

Many amphiphilic molecules can show lyotropic liquid-crystalline phasesequences depending on the volume balances between the hydrophilic partand hydrophobic part. These structures are formed through themicro-phase segregation of two Many amphiphilic molecules can showlyotropic liquid-crystalline phase sequences depending on the volumebalances between the hydrophilic part and hydrophobic part. Thesestructures are formed through the micro-phase segregation of twoincompatible components on a nanometer scale. Soap is an everydayexample of a lyotropic liquid crystal. Certain types of surfactants tendto form lyotropic liquid crystals in emulsions interface (oil-in-water)and exert a stabilizing effect

In one or more embodiments the surfactant is a surfactant or surfactantcombination is capable of or which tends to form liquid crystals.Surfactants which tend to form liquid crystals may improve the qualityof foams. Non-limiting examples of surfactants with postulated tendencyto form interfacial liquid crystals are: phospholipids, alkylglucosides, sucrose esters, sorbitan esters.

In one or more embodiments the at least one surface active agent isliquid. Moreover for the purposes of formulating with liquid ethers aliquid surfactant is preferred

In one or more embodiments the liquid surfactant is a polysorbate,preferably polysorbate 80 or 60.

In one or more embodiments the at least one surface active agent issolid, semi solid or waxy. In a further embodiment they are soluble inoil and in another embodiment have a HLB of less than about 12.

It should be noted that HLB values may not be so applicable to non-ionicsurfactants, for example, with liquid crystals or with silicones. AlsoHLB values may be of lesser significance in a waterless or substantiallywater-free environment.

In one or more embodiments the surfactant can be, a surfactant systemcomprising of a surfactant and a co surfactant, a waxy emulsifier, aliquid crystal emulsifier, an emulsifier which is solid or semi solid atroom temperature and pressure, or combinations of two or more agents inan appropriate proportion as will be appreciated a person skilled in theart. Where a solid or semi solid emulsifier combination is used it canalso comprise a solid or semi solid emulsifier and a liquid emulsifier.In a preferred embodiment at least one surfactant is a liquid.

In one or more embodiments, the surface-active agent includes at leastone non-ionic surfactant. Ionic surfactants are known to be irritants.Therefore, non-ionic surfactants are preferred in applications includingsensitive tissue such as found in most mucosal tissues, especially whenthey are infected or inflamed. Non-ionic surfactants alone can provideformulations and foams of good or excellent quality in the carriers andcompositions.

Thus, in a preferred embodiment, the surface active agent, thecomposition contains a non-ionic surfactant. In another preferredembodiment the composition includes a mixture of non-ionic surfactantsas the sole surface active agent. Yet, in additional embodiments, thefoamable composition includes a mixture of at least one non-ionicsurfactant and at least one ionic surfactant in a ratio in the range ofabout 100:1 to 6:1. In one or more embodiments, the non-ionic to ionicsurfactant ratio is greater than about 6:1, or greater than about 8:1;or greater than about 14:1, or greater than about 16:1, or greater thanabout 20:1. In further embodiments, surface active agent comprises acombination of a non-ionic surfactant and an ionic surfactant, at aratio of between 1:1 and 20:1

In one or more embodiments, a combination of a non-ionic surfactant andan ionic surfactant (such as sodium lauryl sulphate andcocamidopropylbetaine) is employed, at a ratio of between 1:1 and 20:1,or at a ratio of 4:1 to 10:1; for example, about 1:1, about 4:1, about8:1, about 12:1, about 16:1 and about 20:1 or at a ratio of 4:1 to 10:1,for example, about 4:1, about 6:1, about 8:1 and about 10:1.

For foams in selecting a suitable surfactant or combination thereof itshould be borne in mind that the upper amount of surfactant that may beused may be limited by the shakability of the composition. If thesurfactant is non-liquid, it can make the formulation to viscous orsolid. Subject to its miscibility solid surfactants may be added first,and may require gentle warming and then cooling before being combinedwith the other ingredients. In general terms, as the amount ofnon-liquid surfactant is increased the shakability of the formulationreduces until a limitation point is reached where the formulation canbecome non-shakable and unsuitable. Thus in one embodiment, anyeffective amount of surfactant may be used provided the formulationremains shakable. In other certain limited embodiments the upper limitfor foamable formulations may be determined by flowability such that anyeffective amount can be used provided the formulation is sufficientlyflowable to be able to flow through an actuator valve and be releasedand still expand to form a good quality foam. This may be due withoutbeing bound by any theory to one or more of a number of factors such asthe viscosity, the softness, the lack of crystals, the pseudoplastic orsemi pseudo plastic nature of the composition and the dissolution of thepropellant into the composition.

In certain embodiments the amount of surfactant or combination ofsurfactants is between about 0.05% to about 20%; between about 0.05% toabout 15%. or between about 0.05% to about 10%. In a preferredembodiment the concentration of surface active agent is between about0.2% and about 8%. In a more preferred embodiments the concentration ofsurface active agent is between about 1% and about 6% or between about1% and about 4%.

In some embodiments, it is desirable that the surface active agent doesnot contain a polyoxyethylene (POE) moiety, such as polysorbatesurfactants, POE fatty acid esters, and POE alkyl ethers, because theactive agent is incompatible with such surface active agents. Forexample, the active agent pimecrolimus is not stable the presence of POEmoieties, yet benefits greatly from the use of dicarboxylic esters aspenetration enhancers. In such cases, alternative surface active agentsare employed. In an exemplary manner, POE-free surfactants includenon-ethoxylated sorbitan esters, such as sorbitan monopalmitate,sorbitan monostearate, sorbitan tristearate, sorbitan monooleate,sorbitan trioleate, sorbitan monolaurate and sorbitan sesquioleate;glycerol fatty acid esters, such as glycerol monostearate and glycerolmonooleate; mono-, di- and tri-esters of sucrose with fatty acids(sucrose esters), sucrose stearate, sucrose distearate sucrose palmitateand sucrose laurate; and alkyl polyglycosides, such as lauryldiglucoside.

In one or more embodiments, the surface-active agent includes mono-, di-and tri-esters of sucrose with fatty acids (sucrose esters), preparedfrom sucrose and esters of fatty acids or by extraction fromsucro-glycerides. Suitable sucrose esters include those having highmonoester content, which have higher HLB values.

In one or more preferred embodiments the surfactant includes at leastone surfactant selected from a polyoxyethylene fatty ether, apolyoxyethylene fatty ester, a carbohydrate ester and a sucrose ester.

In one or more embodiments non-limiting examples of non-ionicsurfactants include steareth-2, steareth-20, steareth-21, ceteareth 2,PEG-100 stearyl ether, cetearyl glucoside, methyl glucosesesquistearate, sorbitan monostearate, GMS and sorbitan laurate (Span20).

In one or more embodiments non-limiting other examples of surfactantcombinations are glycerol stearate and PEG 100 stearate and laureth 4;steareth 2, PEG 100 stearate and laureth 4; and cetearyl glucoside andcetearyl alcohol.

In an embodiment the surfactant containing formulations are furtherboosted by a foam adjuvant for example stearyl alcohol.

A non-limiting example of a combination of surfactants having a weightedaverage of their HLB values of 11 is glycerol stearate and PEG-100stearate (for example trade name “Simulsol 165” from Sepic).

In some embodiments, the surface active agent is one or more of:glycerol monostearate, polysorbate 80, polysorbate 60, sucrosedistearate, polyoxyl 20 stearyl ether, PEG-2 stearyl ether, PEG 100stearate, PEG 40 stearate (Myrj 52), surcorse stearic acid esters,(Sufhope SE D-1805), cocoglucoside and coconut alcohol (Montanov S), orpolyacrylamide and C13-14 isoparaffin and laureth -7 (Sepigel 305).

Solid Matter Agents

According to an embodiment, the at least one active agent comprisessolid matter or particulate matter i.e., material that is not soluble inthe liquid carrier composition of the foamable composition. Fordefinition purposes, solid matter shall mean material that is notsoluble in the foamable composition more than 10% of the concentrationintended to be included in said foamable composition. The concentrationof the solid matter in the foamable composition is from about 0% toabout 20% w/w. In one or more embodiments, the concentration of solidmatter in the composition is from about 2% to about 16% w/w.

By way of non-limiting examples, the following classes of solid mattersubstances are presented:

Metallic oxides, such as titanium dioxide, zinc oxide, zirconium oxide,iron oxide. Preferably, as used in the present invention, titaniumdioxide has an average primary particle size of from about 15 nm toabout 100 nm, zinc oxide having an average primary particle size of fromabout 15 nm to about 150 nm, zirconium oxide having an average primaryparticle size of from about 15 nm to about 150 nm, iron oxide having anaverage primary particle size of from about 15 nm to about 500 nm, andmixtures thereof. In one embodiment the metal oxides are present in theamount of from about 0.1% to about 20%, preferably from about 0.5% toabout 16%, more preferably from about 1% to about 10%, of thecomposition. In yet another embodiment, such solids are micronized toform particles having primary size of less than 15 nm.

Carbon, for example in the form of amorphous carbon or graphite;

Oxidizing agents, such as benzoyl peroxide, calcium and magnesiumhypochlorite;

Metallic Silver, in small particles, including nanocrystalline silver,which is used for antibacterial and wound healing purposes; other metalparticles and mineral particles;

Cosmetic scrub materials, including, for example meals of strawberryseeds, raspberry seeds, apricot seeds, sweet almond, cranberry seeds;and pigments, which are insoluble in the foamable composition.

Hydrophobic Solvent

Optionally, the foamable carrier further contains at least one otherhydrophobic solvent. In some embodiments, the liquid oil is ahydrophobic solvent. The identification of a “hydrophobic solvent”, asused herein, is not intended to characterize the solubilizationcapabilities of the solvent for any specific active agent or any othercomponent of the foamable composition. Rather, such information isprovided to aid in the identification of materials suitable for use as apart in the foamable compositions described herein.

A “hydrophobic solvent” as used herein refers to a material havingsolubility in distilled water at ambient temperature of less than about1 gm per 100 mL, more preferable less than about 0.5 gm per 100 mL, andmost preferably less than about 0.1 gm per 100 mL.

In one or more embodiments, the hydrophobic organic carrier is an oil,such as mineral oil, MCT oil, isopropyl palmitate, isopropylisostearate, diisopropyl adipate, diisopropyl dimerate, maleated soybeanoil, octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopherylacetate, acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone,glyceryl oleate, tocopheryl linoleate, wheat germ glycerides, arachidylpropionate, myristyl lactate, decyl oleate, propylene glycolricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate,neopentylglycol dicaprylate/dicaprate, isononyl isononanoate,isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyldodecanol, unsaturated or polyunsaturated oils, such as olive oil, cornoil, soybean oil, canola oil, cottonseed oil, coconut oil, sesame oil,sunflower oil, borage seed oil, syzigium aromaticum oil, hempseed oil,herring oil, cod-liver oil, salmon oil, flaxseed oil, wheat germ oil,evening primrose oils; essential oils; and silicone oils, such asdimethicone, cyclomethicone, polyalkyl siloxanes, polyaryl siloxanes,polyalkylaryl siloxanes and polyether siloxane copolymers,polydimethylsiloxanes (dimethicones) andpoly(dimethylsiloxane)-(diphenyl-siloxane) copolymers.

One class of hydrophobic solvents includes polyunsaturated oils,containing omega-3 and omega-6 fatty acids, which are know to possesstherapeutic properties through different modes of action. Examples ofsuch polyunsaturated fatty acids are linoleic and linolenic acid,gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA). Thus, in one preferred embodiment the atleast one hydrophobic solvent comprises at least 6% of an oil selectedfrom omega-3 oil, omega-6 oil, and mixtures thereof.

Another preferred class of hydrophobic solvents comprises the essentialoils, which are considered “therapeutic oils”, which contain activebiologically occurring molecules and, upon topical application, exert atherapeutic effect. Examples of such oils are rosehip oil, which containretinoids and is known to reduce acne and post-acne scars, tea tree oil,which possesses anti-microbial activity including antibacterial,antifungal and antiviral properties. Other examples of essential oilsare basil, camphor, cardamom, carrot, citronella, clary sage, clove,cypress, frankincense, ginger, grapefruit, hyssop, jasmine, lavender,lemon, mandarin, marjoram, myrrh, neroli, nutmeg, petitgrain, sage,tangerine, vanilla, verbena, as well as any other therapeuticallybeneficial oil known in the art of herbal medication.

Emollients

A further class of solvents present in some embodiments are “emollients”that have a softening, refatting, or soothing effect, especially whenapplied to body areas, such as the skin and mucosal surfaces. Emollientsare not necessarily hydrophobic. Without derogating the generality ofthis definition, examples of suitable emollients for use include but arenot limited to mineral oil, lanolin oil, coconut oil, cocoa butter,cocoglycerides, olive oil, aloe vera extract, jojoba oil, castor oil,fatty acids, fatty alcohols, diisopropyl adipate, hydroxybenzoateesters, benzoic acid esters of C9 to C15 alcohols, isononyliso-nonanoate, isopropyl myristate, silicone oils, polyethers, C12 toC15 alkyl benzoates, oleic acid, stearic fatty acid, cetyl alcohols,hexadecyl alcohol, dimethyl polysiloxane, polyoxypropylene cetyl ether,polyoxypropylene butyl ether, hexyleneglycol, propylene glycol,isostearic acid derivatives, isopropyl palmitate, isopropyl isostearate,diisopropyl adipate, diisopropyl dimerate, maleated soybean oil, octylpalmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate,acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryloleate, tocopheryl linoleate, wheat germ glycerides, arachidylpropionate, myristyl lactate, decyl oleate, propylene glycolricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate,neopentylglycol dicaprylate/dicaprate, isononyl isononanoate,isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyldodecanol, sucrose esters of fatty acids, octyl hydroxystearate and, andderivatives, esters, salts and mixtures thereof. Examples of othersuitable emollients may be found in the Cosmetic Bench Reference, pp.1.19-1.22 (1996) and in similar publications. In an embodiment, the oilysolvent component is an emollient.

Foam Adjuvant

Optionally, a foam adjuvant is included in the foamable carriers toincrease the foaming capacity of surfactants and/or to stabilize thefoam. In one or more embodiments, the foam adjuvant agent includes fattyalcohols having 14 or more carbons in their carbon chain, such as cetylalcohol and stearyl alcohol (or mixtures thereof). Other examples offatty alcohols are arachidyl alcohol (C20), behenyl alcohol (C22),1-triacontanol (C30), as well as alcohols with longer carbon chains (upto C50). Fatty alcohols, derived from beeswax and including a mixture ofalcohols, a majority of which has at least 20 carbon atoms in theircarbon chain, are especially well suited as foam adjuvant agents. Theamount of the fatty alcohol required to support the foam system isinversely related to the length of its carbon chains. Foam adjuvants, asdefined herein are also useful in facilitating improved spreadabilityand absorption of the composition.

In one or more embodiments, the foam adjuvant agent includes fatty acidshaving 16 or more carbons in their carbon chain, such as hexadecanoicacid (C16) stearic acid (C18), arachidic acid (C20), behenic acid (C22),octacosanoic acid (C28), as well as fatty acids with longer carbonchains (up to C50), or mixtures thereof. As for fatty alcohols, theamount of fatty acids required to support the foam system is inverselyrelated to the length of its carbon chain.

Optionally, the carbon atom chain of the fatty alcohol or the fatty acidmay have at least one double bond. A further class of foam adjuvantagent includes a branched fatty alcohol or fatty acid. The carbon chainof the fatty acid or fatty alcohol also can be substituted with ahydroxyl group, such as 12-hydroxy stearic acid.

In a preferred embodiment the foam adjuvant is a solid, wax or powder atroom temperature. In certain embodiments where two or more foamadjuvants are used at least one should be a solid, wax or powder at roomtemperature. In some embodiments, the foam adjuvant is a solid fattyalcohol. Examples of solid fatty alcohols include, without limitation,stearyl alcohol, cetyl alcohol, cetostearyl alcohol, myristyl alcohol,palmitoleyl alcohol, arachidyl alcohol and behenyl alcohol

In some embodiments, the foam adjuvant is oleyl alcohol.

Substantially Alcohol Free

Lower or short chain alcohols, having up to 5 carbon atoms in theircarbon chain skeleton, such as ethanol, propanol, isopropanol, butanol,iso-butanol, t-butanol and pentanol are considered less desirablesolvents or co-solvents due to their skin-irritating effect. Thus,according to some embodiments, the composition is substantiallyalcohol-free i.e., free of short chain alcohols. In other embodiments,the composition comprises less than about 5% final concentration oflower alcohols, preferably less than 2%, more preferably less than 1%.

Potent Solvent

In one or more embodiments, the foamable composition includes a potentsolvent, in addition to the hydrophobic solvents, polar solvents oremollients of the composition. A potent solvent is a solvent other thanmineral oil that solubilizes a specific active agent substantiallybetter than a hydrocarbon solvent such as mineral oil or petrolatum. Forexample, a potent solvent solubilizes the active agent 5 fold betterthan a hydrocarbon solvent; or even solubilizes the active agent 10-foldbetter than a hydrocarbon solvent.

A non-limiting exemplary list of solvents that can be considered aspotent solvents includes polyethylene glycol, propylene glycol, hexyleneglycol, butanediols and isomers thereof, glycerol, benzyl alcohol, DMSO,ethyl oleate, ethyl caprylate, diisopropyl adipate, dimethylacetamide,N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone,isosorbide derivatives, such as dimethyl isosorbide, glycofurol andethoxydiglycol (transcutol) and laurocapram.

The use of a potent solvent in a foam composition provides an improvedmethod of delivering poorly soluble therapeutic agents to a target area.It is known that low drug solubility results in poor bioavailability,leading to decreased effectiveness of treatment. Foam compositions, forwhich the solvent includes a potent solvent, increase the levels of theactive agent in solution and thus, provide high delivery and improvedtherapy.

In one or more embodiments, the PPG alkyl ether may act as a potentsolvent.

Modulating Agent

In one or more embodiments the modulating agent is used in a uniquewaterless liquid oil with silicone.

The term modulating agent is used to describe an agent which can improvethe stability of or stabilize a carrier or a foamable composition and/oran active agent by modulating the effect of a substance or residuepresent in the carrier or composition. The substance or residue may forexample be acidic or basic and potentially alter an artificial pH in awaterless or substantially non-aqueous environment or it may be one ormore metal ions which may act as a potential catalyst in a waterless orsubstantially non-aqueous environment or it may be an ionisation agentor it may be an oxidizing agent.

In the embodiment modulating agent is used to describe an agent whichcan effect pH in an aqueous solution. the term modulating agent moreparticularly means an acid or base or buffer system or combinationsthereof, which is introduced into or is present in and acts to modulatethe ionic or polar characteristics and any acidity or basesity balanceof a waterless or substantially non-aqueous carrier, composition,foamable carrier or foamable composition or resultant foam.

In an embodiment, the modulating or additional component is a pHadjusting agent or a buffering agent.

The agent can be any of the known buffering systems used inpharmaceutical or cosmetic formulations as would be appreciated by a manof the art. It can also be an organic acid, a carboxylic acid, a fattyacid an amino acid, an aromatic acid, an alpha or beta hydroxyl acid anorganic base or a nitrogen containing compound.

In one or more further embodiments the modulating agent is used todescribe an agent, which is a chelating or sequestering or complexingagent that is sufficiently soluble or functional in the waterlesssolvent to enable it to “mop up” or “lock” metal ions.

In one or more embodiments the chelating agent is selected from thegroup consisting of acetyl trihexyl citrate, aminotrimethylenephosphonic acid, beta-alanine diacetic acid, bismuth citrate, calciumdisodium edta, citric acid, cyclohexanediamine tetraacetic acid,diammonium citrate, dibutyl oxalate, diethyl oxalate, diisobutyloxalate, diisopropyl oxalate, dilithium oxalate, dimethyl oxalate,dipotassium edta, dipotassium oxalate, dipropyl oxalate, disodium edta,disodium edta-copper, disodium pyrophosphate, edta, etidronic acid,hedta, methyl cyclodextrin, oxalic acid, pentapotassium, triphosphate,pentasodium aminotrimethylene phosphonate, pentasodium pentetate,pentasodium triphosphate, pentetic acid, phytic acid, potassium citrate,sodium citrate, sodium dihydroxyethylglycinate, sodium gluceptate,sodium gluconate, sodium hexametaphosphate, sodium metaphosphate, sodiummetasilicate, sodium oxalate, sodium trimetaphosphate, tea-edta,tetrahydroxypropyl ethylenediamine, tetrapotassium etidronate,tetrapotassium pyrophosphate, tetrasodium edta, tetrasodium etidronate,tetrasodium pyrophosphate, tripotassium edta, trisodium edta, trisodiumhedta, trisodium nta, trisodium phosphate, malic acid, fumaric acid,maltol, succimer, penicillamine, dimercaprol, and desferrioxaminemelate.

Modulating agents may be added to the compositions of the subjectinvention, preferably from about 0.1% to about 10%, more preferably fromabout 1% to about 5%, of the composition. Where the active agent itselfis the modulating agent alone or in combination with another modulatingagent it will be added at an effective dose which may be outside theseranges. For example azaleic acid may be at about 15% of the composition.

Further detail regarding modulating agents is found in co-pendingPublished U.S. Patent Application 2008/0206159, which is herebyincorporated in its entirety by reference.

The substance or residue can be introduced into the formulation from anyone or more of the ingredients, some of which themselves may have acidicor basic properties. For example the polymer or solvent may containbasic residues in which case it may be desirable or beneficial to add anacid. Alternatively the surfactant may contain some acid residues inwhich case the addition of a base may be desirable and beneficial. Insome cases more than one ingredient may contain residues which mayameliorate or compound their significance. For example if one ingredientprovided weak acid residues and another stronger acid residues theartificial pH in a waterless environment should be lower. In contrast,if one residue was acid and the other basic the net effect in theformulation maybe significantly reduced. In some circumstances theactive ingredient may favor an acidic pH or more significantly may needto be maintained at a certain acidic pH otherwise it may readilyisomerize, chemically react or breakdown, in which case introducingacidic components might be of help. Likewise in some circumstances theactive ingredient may favor a basic pH or more significantly may need tobe maintained at a certain basic pH otherwise it may readily hydrolyse,undergo rearrangement, isomerize, chemically react or breakdown, inwhich case introducing basic components might be of help. In anembodiment sufficient modulating agent is added to achieve an artificialpH in which the active agent is preferably stable. Such artificial pHmay be acidic, maybe basic or may be neutral.

The modulating agent to the foamable composition is useful forstabilizing pharmaceutical and cosmetic active agents which are unstablein certain pH conditions. It is known, for example, that active agents,which contain ester bond in their structure tend to undergo hydrolysisof the ester bond at basic pH levels. Therefore, the addition of anagent which avoids the formation of basic pH condition and thus,prevents degradation of such active agents. Many steroid compounds areknown to undergo rearrangement at high pH, and again, adding an acidicmodulating agent helps prevent such degradation. Another example of apH-sensitive active agent is vitamin D, which degrades at low pH levels.In such a case, the addition of a basic modulating agent, such astriethanol amine is useful to maintain acceptable stability of thisactive agents.

It is important to maintain skin surface pH in order to preventsusceptibility to bacterial skin infections or skin damage and disease.Thus, adding a modulating agent, which contributes to the stabilizationof skin pH at the desirable level, is advantageous.

In the same fashion, adding an acidic modulating agent to a foamablecomposition, which is intended for vaginal application is advantageous,since the best protection against vaginal infection is attained in pHlower than 4.

Anti-Oxidants/Radical Scavengers

In one or more embodiments, the modulating agent may also be apreservative or an antioxidant or an ionization agent. Any preservative,antioxidant or ionization agents suitable for pharmaceutical or cosmeticapplication may be used. Non-limiting examples of antioxidants aretocopherol succinate, propyl galate, butylated hydroxy toluene and butylhydroxy anisol. Ionization agents may be positive or may be negativedepending on the environment and the active agent or composition that isto be protected. Ionization agents may for example act to protect orreduce sensitivity of active agents. Non-limiting examples of positiveionization agents are benzyl conium chloride, and cetyl pyridiumchloride. Non-limiting examples of negative ionization agents are sodiumlauryl sulphate, sodium lauryl lactylate and phospholipids.

A safe and effective amount of an anti-oxidant/radical scavenger may beadded to the compositions of the subject invention, preferably fromabout 0.1% to about 10%, more preferably from about 1% to about 5%, ofthe composition.

Anti-oxidants/radical scavengers such as ascorbic acid (vitamin C) andits salts, ascorbyl esters of fatty acids, ascorbic acid derivatives(e.g., magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbylsorbate), tocopherol (vitamin E), tocopherol sorbate, tocopherolacetate, other esters of tocopherol, butylated hydroxy benzoic acids andtheir salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid(commercially available under the tradename Rolex), gallic acid and itsalkyl esters, especially propyl gallate, uric acid and its salts andalkyl esters, sorbic acid and its salts, lipoic acid, amines (e.g.,N,N-diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (e.g.,glutathione), dihydroxy fumaric acid and its salts, lycine pidolate,arginine pilolate, nordihydroguaiaretic acid, bioflavonoids, curcumin,lysine, methionine, proline, superoxide dismutase, silymarin, teaextracts, grape skin/seed extracts, melanin, and rosemary extracts maybe used.

In one or more embodiments the modulating agent is a flavonoid.

A non-limiting list of flavonoid compounds is: benzquercin, diosmin,ethoxazorutoside, flavodate, sodium hesperidin, leucocianido,monoxerutin, oxerutin, quercetin, rutoside, rosmarinic acid. The aboveinformation was noted from Dietary Supplements, Electronic Version,Pharmaceutical Press 2007. In an embodiment the flavanoid includesquercitin and/or rutin. In certain embodiments the flavonoids actsynergistically with each other or with other actives.

Microsponges

Microsponges are rigid, porous and spongelike round microscopicparticles of cross-linked polymer beads (e.g., polystyrene or copolymersthereof), each defining a substantially noncollapsible pore network.Microsponges can be loaded with an active ingredient and can provide acontrolled time release of the active ingredient to skin or to a mucosalmembrane upon application of the formulation. The slow release isintended to reduce irritation by the active. Microsponge® deliverytechnology was developed by Advanced Polymer Systems. In one or moreembodiments the composition comprises one or more active agents loadedinto Microsponges with a waterless carrier described herein which maycomprise a modulating agent.

Humectant

A humectant, is a substance that helps retain moisture and also preventsrapid evaporation. Non-limiting examples of suitable humectants arepropylene glycol, propylene glycol derivatives, and glycerin. Furtherhumectants include but are not limited to guanidine, urea, glycolicacid, glycolate salts, ammonium glycolate, quaternary alkyl ammoniumglycolate, lactic acid, lactate salts, ammonium lactate, quaternaryalkyl ammonium lactate, aloe vera, aloe vera gel, allantoin, urazole,alkoxylated glucose, hyaluronic acid, lactamide monoethanolamine,acetamide monoethanolamine and derivatives, esters, salts and mixturesthereof.

Other examples of humectants and moisturizers may be found in theHandbook of Pharmaceutical Additives published by Gower. Suitable onesfor use with and soluble in the waterless compositions may be selectedas will be appreciated by a person skilled in the art.

Moisturizers

A moisturizer, is a substance that helps retain moisture or add backmoisture to the skin. Examples are allantoin, petrolatum, urea, lacticacid, sodium PCV, glycerin, shea butter, caprylic/capric/stearictriglyceride, candelilla wax, propylene glycol, lanolin, hydrogenatedoils, squalene, sodium hyaluronate and lysine PCA. Glycerine and sodiumpCA work in combination. Other examples may be found in the Handbook ofPharmaceutical Additives published by Gower.

Pharmaceutical compositions may in one or more embodiments usefullycomprise in addition a humectant or a moisturizer or combinationsthereof.

Additional Components

In an embodiment, a composition includes one or more additionalcomponents. Such additional components include but are not limited toanti perspirants, anti-static agents, buffering agents,anti-oxidants/free radical scavengers, bulking agents, chelating agents,cleansers, colorants, conditioners, deodorants, diluents, dyes,emollients, fragrances, hair conditioners, humectants, pearlescent aids,perfuming agents, permeation enhancers, pH-adjusting agents, occlusiveagents, preservatives, protectants, skin penetration enhancers,softeners, solubilizers, sunscreens, sun blocking agents, sunlesstanning agents, viscosity modifiers and vitamins. As is known to oneskilled in the art, in some instances a specific additional componentmay have more than one activity, function or effect.

In an embodiment, the additional component is a pH adjusting agent or abuffering agent. Suitable buffering agents include but are not limitedto acetic acid, adipic acid, calcium hydroxide, citric acid, glycine,hydrochloric acid, lactic acid, magnesium aluminometasilicates,phosphoric acid, sodium carbonate, sodium citrate, sodium hydroxide,sorbic acid, succinic acid, tartaric acid, and derivatives, salts andmixtures thereof.

In an embodiment, the additional component is a humectant.

In an embodiment no preservative is added because the formulation is awaterless oil-based formulation having an Aw (Water Activity) value ofless than 0.5 which is below the level of microbial proliferation. Incertain limited embodiments, the additional component is an oil solublepreservative. Suitable preservatives include but are not limited to C12to C15 alkyl benzoates, alkyl p-hydroxybenzoates, castor oil, cetylalcohols, chlorocresol, cocoa butter, coconut oil, diisopropyl adipate,dimethyl polysiloxane, fatty acids, fatty alcohols, hexadecyl alcohol,jojoba oil, lanolin oil, mineral oil, oleic acid, olive oil,polyoxypropylene butyl ether, polyoxypropylene cetyl ether, siliconeoils, stearic fatty acid, vitamin E, vitamin E acetate and derivatives,esters, salts and mixtures thereof.

In an embodiment, the additional component is a skin penetrationenhancer.

Propellants

Examples of suitable propellants include volatile hydrocarbons such asbutane, propane, isobutane and fluorocarbon gases, or mixtures thereof.

In an embodiment the propellant is 1681, which is a mixture of propane,isobutene and butane. In another embodiment it is AP 70, which is amixture of propane, isobutene and butane with a higher pressure.

The propellant makes up about 3-25 wt % of the foamable composition. Insome circumstances the propellant may be up to 35%. Thus, in someembodiments, the ratio of the liquefied or compressed gas propellant tothe other components of the formulation ranges from about 3:100 to about25:100 by weight, from about 3:100 to about 35:100, or from about 3:100to about 45:100. In some embodiments, the ratio of the liquefied orcompressed gas propellant to the other components of the formulation isat least about 3:100, at least about 10:100, at least about 15:100, atleast about 20:100, or at least about 25:100. The propellants are usedto generate and administer the foamable composition as a foam. The totalcomposition including propellant, foamable compositions and optionalingredients is referred to as the foamable composition.

Alcohol and organic solvents render foams inflammable. It has beensurprisingly discovered that fluorohydrocarbon propellants, other thanchloro-fluoro carbons (CMCs), which are non-ozone-depleting propellants,are particularly useful in the production of a non-flammable foamablecomposition. A test according to European Standard prEN 14851, titled“Aerosol containers—Aerosol foam flammability test” revealed thatcompositions containing an organic carrier that contains a hydrophobicorganic carrier and/or a solvent, which are detected as inflammable whena hydrocarbon propellant is used, become non-flammable, while thepropellant is an HFC propellant.

Such propellants include, but are not limited to, hydrofluorocarbon(HFC) propellants, which contain no chlorine atoms, and as such, fallcompletely outside concerns about stratospheric ozone destruction bychlorofluorocarbons or other chlorinated hydrocarbons. Exemplarynon-flammable propellants according to this aspect include propellantsmade by DuPont under the registered trademark Dymel, such as 1,1,1,2tetrafluorethane (Dymel 134), and 1,1,1,2,3,3,3 heptafluoropropane(Dymel 227) 1,1, difluoro ethane (Dymel 152) and 1,1,1,3,3,3hexafluoropropane HFCs possess Ozone Depletion Potential of 0.00 andthus, they are allowed for use as propellant in aerosol products.

Notably, the stability of foamable emulsions including HFC as thepropellant can be improved in comparison with the same composition madewith a hydrocarbon propellant.

In one or more embodiments foamable compositions comprise a combinationof a HFC and a hydrocarbon propellant such as n-butane or mixtures ofhydrocarbon propellants such as propane, isobutane and butane. Wheremixtures are used they can be selected to generate different levels ofpressure. For example 1681 has a lower pressure than AP 40 which islower than that provided by propane alone. The amount and pressure ofthe propellant is selected to provide foam release without powerful jetsand without tailing such that the foam is released in ideally asubstantially single unbroken pulse,

In one or more embodiments “liquification” occurs following adding thepropellant, which in turn will affect the viscosity substantially orradically. Thus in one or more embodiments the oil with siliconecompositions are liquefied or further liquefied by the propellant.

Composition and Foam Physical Characteristics and Advantages

A pharmaceutical or cosmetic composition manufactured using the foamablecarrier is very easy to use. When applied onto the body surface ofmammals, i.e., humans or animals, it is in a foam state, allowing freeapplication without spillage. Upon further application of a mechanicalforce, e.g., by rubbing the composition onto the body surface, it freelyspreads on the surface and is rapidly absorbed.

The foamable composition is stable, having an acceptable shelf-life ofat least one year, or preferably, at least two years at ambienttemperature, as revealed in accelerated stability tests. Organiccarriers and propellants tend to impair the stability of emulsions andto interfere with the formation of stable foam upon release from apressurized container. It has been observed, however, that the foamablecompositions according to the present invention are surprisingly stable.Following accelerated stability studies, they demonstrate desirabletexture; they form fine bubble structures that do not break immediatelyupon contact with a surface, spread easily on the treated area andabsorb quickly.

The composition should also be free flowing, to allow it to flow throughthe aperture of the container, e.g., and aerosol container, and createan acceptable foam.

Quantitative and Qualitative

Foam Quality

Foam quality can be graded as follows:

Grade E (excellent): very rich and creamy in appearance, does not showany bubble structure or shows a very fine (small) bubble structure; doesnot rapidly become dull; upon spreading on the skin, the foam retainsthe creaminess property and does not appear watery.

Grade G (good): rich and creamy in appearance, very small bubble size,“dulls” more rapidly than an excellent foam, retains creaminess uponspreading on the skin, and does not become watery.

Grade FG (fairly good): a moderate amount of creaminess noticeable,bubble structure is noticeable; upon spreading on the skin the productdulls rapidly and becomes somewhat lower in apparent viscosity.

Grade F (fair): very little creaminess noticeable, larger bubblestructure than a “fairly good” foam, upon spreading on the skin itbecomes thin in appearance and watery.

Grade P (poor): no creaminess noticeable, large bubble structure, andwhen spread on the skin it becomes very thin and watery in appearance.

Grade VP (very poor): dry foam, large very dull bubbles, difficult tospread on the skin.

Topically administrable foams are typically of quality grade E or G,when released from the aerosol container. Smaller bubbles are indicativeof more stable foam, which does not collapse spontaneously immediatelyupon discharge from the container. The finer foam structure looks andfeels smoother, thus increasing its usability and appeal.

Foam Physical Characteristics

In terms of foam consistency and texture an acceptable foam is one, thatexhibits the following characteristics:

Upon release from an aerosol can, creates a foam mass, which issustained on a surface for at least one minute, more preferably at leasttwo minutes, and yet more preferably for at least 3 minutes or more, sayeven about 5 minutes.

Foam texture should vary from a very fine creamy foam to a fine bubblestructure.

In terms of spreadability and absorption an acceptable foam is one, thatdoes not readily collapse upon dispensing on the skin; spreads easily ona skin surface; at least partially absorbed following rubbing onto theskin, and more preferably, substantially absorbed following rubbing onthe skin.

In terms of tactile properties an acceptable foam is one, that: createsa pleasant feeling after application; leaves minimal oily residue; andleaves minimal shiny residual look.

Foam Collapse

A further aspect of the foam is breakability. Thermally sensitive foamsimmediately collapse upon exposure to skin temperature and, therefore,cannot be applied on the hand and afterwards delivered to the afflictedarea.

The foam has several notable advantages, when compared withhydroalcoholic foam compositions, such as

-   -   (1) Breakability. The foam is thermally stable and breakable        under sheer force but is not “quick breaking which allows        comfortable application and well directed administration to the        target area;    -   (2) Skin drying and skin barrier function. Short chain alcohols        are known to dry the skin and impair the integrity of the skin        barrier. By contrast, having an liquid oil in the composition        protects and improves moisturization and does not cause unwanted        skin barrier damage.    -   (3) Irritability. Due to the lack of lower alcohols (C1-C5) and        improvement in skin barrier function, the use of non-ionic        surfactants, the presence of silicone and improvement in skin        barrier function, skin irritability is eliminated.    -   (4) Dry feeling. The presence of silicone can significantly        reduce alleviate or overcome the dry (no water) feeling of        waterless formulations possibly due to its lubricating property        and it may also ameliorate the oily feeling of the carrier.        Moreover, the change in nature from an oily fluid to a        relatively low density foam also can have a positive effect on        skin or body cavity feeling.

Another property of the foam is specific gravity, as measured uponrelease from the aerosol can. Typically, oily foams have specificgravity of less than 0.20 g/mL; or less than 0.15 g/mL; or less than0.12 g/mL, depending on their composition and on the propellantconcentration. Preferably, specific gravity is in the range of about0.05 gr/mL to about 0.20 gr/mL, more preferably between about 0.07 gr/mLand about 0.15 gr/mL.

Pharmaceutical Composition

The foamable composition is an ideal vehicle for active pharmaceuticalingredients and/or active cosmetic ingredients. In the context, activepharmaceutical ingredients and active cosmetic ingredients arecollectively termed “active agent” or “active agents”. The silicone andoil waterless formulations optionally coupled with the use of modulatingagents can uniquely be adapted to protect and preserve active agentswhen stored in compatible sealed canisters with propellant A foamablecomposition, comprising an active agent has the following advantages:

-   -   1. The foamable composition provides a preferred solvent for        active agents, particularly for poorly soluble or        water-insoluble agents.    -   2. The provision of an essentially single phase foamable        composition facilitates a co-solvent effect, resulting increased        concentrations of soluble active agent in the dosage form, thus        facilitating enhanced skin penetration of the active agent. In        many cases, increased penetration is positively correlated with        improved clinical outcome. In certain case, attaining an        increased drug penetration into the target site of action        enables a decrease of treatment frequency, for example, from        twice or three times daily to once daily. Oils with a secondary        solvent can act as skin penetration enhancers, thus, increasing        drug residence time in the target area and increasing clinical        efficacy, as detailed above.    -   3. The fact that the composition contains no or little water,        minimizes the probability of degradation of water-sensitive        active agents. Furthermore, as exemplified herein, a foam        containing an oil and a silicone with no water at all can be        formed in accordance with the composition and process. Such        compositions ensure high stability of water sensitive active        agents.    -   4. The foamable silicone and oil composition is contained in an        impermeable pressurized packaging presentation is impermeable        and thus, the active agent is not exposed to environmental        degradation factors, such as light and oxidating agent during        storage.

Thus, in one or more embodiments, the foamable composition includes atleast one therapeutic agent, in a therapeutically effectiveconcentration. Therapeutic agents are described herein. In addition,compounds disclosed in International Patent Publication No. WO2004/03284, which is incorporated by reference in its entirety aresuitable for use in the pharmaceutical compositions described herein.

In an embodiment the therapeutic agent is soluble in the foamablecomposition. In alternative embodiments the therapeutic agent ispartially soluble and in further embodiments the therapeutic agent isinsoluble in the formulation. Where the agent is insoluble or partiallysoluble it is provided as a homogenous suspension. In certainembodiments the homogeneous suspension remains homogenous over asubstantial period of time suitable for pharmaceutical use. In otherembodiments the agent may cram or separate out but homogeneity is fullyreversible on shaking.

Oil soluble active agents may be readily used in the oil/siliconesurfactant compositions described herein. A short list of non limitingexamples of oil soluble active agents include calcipotriol, calcitriol,ciclopiroxolamine, benzocaine. Other examples are terbinofine,diclofenac, tacrolimus and pimecrolimus and also oil soluble vitamins.Estradiol, progesterone are non limiting examples of sparingly oilsoluble agents.

Because the prefoam formulations can provide a substantially waterless,high oil content environment, particular classes of activepharmaceutical ingredients (APIs) will benefit from their inclusion inthe composition. For example, active agents that are water sensitive,such as minocycline, doxycycline and other tetracycline drugs, vitamin D(e.g., calcipotriol and calcitriol), can have improved stability in thewaterless composition. API's that are esters or amides are generallyprone to hydrolysis by water and would benefit from a water free oilenvironment. API's that are sensitive to free radical attack oroxidation also would benefit from a water free oil environment.Similarly, active agents that are sensitive to specific pH level (whichprevails in the presence of water) will also benefit. Exemplary APIsthat would benefit from the silicone waterless compositions according toone or more embodiments include Vitamin D analogs and derivatives thatdegrade at low pH and corticosteroids that degrade at high pH. Oilsoluble drugs can also be included in the compositions, such ascorticosteroids, immunomodulators, such as tacrolimus and pimecrolimus,oil-soluble vitamins, e.g., vitamin A and derivatives thereof, otherretinoids, vitamin E. Certain APIs may possess more than one of theabove features, and thereby benefit even further from the siliconewaterless compositions.

In one or more embodiments, the at least one therapeutic agent isselected from the group consisting of a steroidal antiinflammatoryagent, a nonsteroidal anti-inflammatory drug, an immunosuppressiveagent, an immunomodulator, an immunoregulating agent, a hormonal agent,an antibiotic agent, an antifungal agent, an antiviral agent, anantiparasitic agent, a vasoactive agent, a vasoconstrictor, avasodilator, vitamin A, a vitamin A derivative, vitamin B, a vitamin Bderivative, vitamin C, a vitamin C derivative, vitamin D, a vitamin Dderivative, vitamin E, a vitamin E derivative, vitamin F, a vitamin Fderivative, vitamin K, a vitamin K derivative, a wound healing agent, adisinfectant, an anesthetic, an antiallergic agent, an alpha hydroxylacid, lactic acid, glycolic acid, a beta-hydroxy acid, a protein, apeptide, a neuropeptide, a allergen, an immunogenic substance, ahaptene, an oxidizing agent, an antioxidant, a dicarboxylic acid,azelaic acid, sebacic acid, adipic acid, fumaric acid, an antibioticagent, an antiproliferative agent, an anticancer agent, a photodynamictherapy agent, an anti-wrinkle agent, a radical scavenger, a metal oxide(e.g., titanium dioxide, zinc oxide, zirconium oxide, iron oxide),silicone oxide, an anti wrinkle agent, a skin whitening agent, a skinprotective agent, a masking agent, an anti-wart agent, a refattingagent, a lubricating agent and mixtures thereof.

In certain cases, the disorder to be treated involves unaestheticlesions that need to be masked. For example, rosacea involves papulesand pustules, which can be treated with an antibiotic agent, as well aserythema, telangiectasia and redness, which partially respond totreatment with an antibiotic agent. Thus, in one or more embodiments,the additional active agent is a masking agent, i.e., a pigment.Non-limiting examples of suitable pigments include brown, yellow or rediron oxide or hydroxides, chromium oxides or hydroxides, titanium oxidesor hydroxides, zinc oxide, FD&C Blue No. 1 aluminum lake, FD&C Blue No.2 aluminum lake and FD&C Yellow No. 6 aluminum lake.

Suitable active agents include but are not limited to active herbalextracts, acaricides, age spot and keratose removing agents, allergen,analgesics, local anesthetics, antiacne agents, antiallergic agents,antiaging agents, antibacterials, antibiotics, antiburn agents,anticancer agents, antidandruff agents, antidepressants, antidermatitisagents, antiedemics, antihistamines, antihelminths, antihyperkeratolyteagents, antiinflammatory agents, antiirritants, antilipemics,antimicrobials, antimycotics, antiproliferative agents, antioxidants,anti-wrinkle agents, antipruritics, antipsoriatic agents, antirosaceaagents antiseborrheic agents, antiseptic, antiswelling agents, antiviralagents, antiyeast agents, astringents, topical cardiovascular agents,chemotherapeutic agents, corticosteroids, dicarboxylic acids,disinfectants, fungicides, hair growth regulators, hormones, hydroxyacids, immunosuppressants, immunoregulating agents, insecticides, insectrepellents, keratolytic agents, lactams, metals, metal oxides,mitocides, neuropeptides, non-steroidal anti-inflammatory agents,oxidizing agents, pediculicides, photodynamic therapy agents, retinoids,sanatives, scabicides, self tanning agents, skin whitening agents,vasoconstrictors, vasodilators, vitamins, vitamin D derivatives, woundhealing agents and wart removers. As is known to one skilled in the art,in some instances a specific active agent may have more than oneactivity, function or effect.

In an embodiment, the active agent is an active herbal extract. Suitableactive herbal extracts include but are not limited to angelica, aniseoil, astragali radix, azalea, benzyl acetate, birch tar oil, bornylacetate, cacumen biotae, camphor, cantharidin, capsicum, cineole,cinnamon bark, cinnamon leaf, citronella, citroneliol, citronellylacetate, citronellyl formate, eucalyptus, eugenyl acetate, floscarthami, fructus mori, garlic, geraniol, geranium, geranyl acetate,habanera, isobutyl angelicate, lavender, ledum latifolium, ledumpalustre, lemongrass, limonene, linalool, linalyl acetate, methylanthranilate, methyl cinnamate, mezereum, neem, nerol, neryl acetate,nettle root extract, oleum ricini, oregano, pinenes, .alpha.-pinene,.beta.-pinene, radix angelicae sinesis, radix paenoiae rubra, radixpolygoni multiflori, radix rehmanniae, rhizoma pinelliae, rhizomazingiberis recens, sabadilla, sage, sandalwood oil, saw palmettoextract, semen sesami nigrum, staphysagria, tea tree oil, terpenealcohols, terpene hydrocarbons, terpene esters, terpinene, terpineol,terpinyl acetate and derivatives, esters, salts and mixtures thereof. Inan embodiment, the active agent is an acaricide. Suitable acaricidesinclude but are not limited to amitraz, flumethrin, fluvalinate andderivatives, esters, salts and mixtures thereof.

In an embodiment, the active agent is an age spot and keratoses removingagent. Suitable age spot and keratoses removing agent include but arenot limited to hydroxy acids, azelaic acid and other relateddicarboxylic acids, retinoids, kojic acid, arbutin, nicotinic, ascorbicacid, hydroquinone and derivatives, esters, salts and mixtures thereof.Certain nonsteroidal anti-inflammatory agents, such as diclofenac arealso useful for the treatment of keratoses.

In an embodiment, the active agent is an analgesic. Suitable analgesicsinclude but are not limited to benzocaine, butamben picrate, dibucaine,dimethisoquin, dyclonine, lidocaine, pramoxine, tetracaine, salicylatesand derivatives, esters, salts and mixtures thereof.

In an embodiment, the active agent is a local anesthetic. Suitable localanesthetics include but are not limited to benzocaine, benzyl alcohol,bupivacaine, butamben picrate, chloroprocaine, cocaine, dibucaine,dimethisoquin, dyclonine, etidocaine, hexylcaine, ketamine, lidocaine,mepivacaine, phenol, pramoxine, procaine, tetracaine, salicylates andderivatives, esters, salts and mixtures thereof.

In an embodiment, the active agent is an antiacne agent. Suitableantiacne agents include but are not limited to N-acetylcysteine,adapalene, azelaic acid, benzoyl peroxide, cholate, clindamycin,deoxycholate, erythromycin, flavinoids, glycolic acid, meclocycline,metronidazol, mupirocin, octopirox, phenoxy ethanol, phenoxy propanol,pyruvic acid, resorcinol, retinoic acid, salicylic acid, scymnolsulfate, sulfacetamide-sulfur, sulfur, tazarotene, tetracycline,tretinoin triclosan and derivatives, esters, salts and mixtures thereof.

In an embodiment, the active agent is an antiaging agent. Suitableantiaging agents include but are not limited to sulfur-containing D andL amino acids, alpha-hydroxy acids, beta-hydroxy acids (e.g. salicylicacid), urea, hyaluronic acid, phytic acid, lipoic acid; lysophosphatidicacid, skin peel agents (e.g., phenol, resorcinol and the like), vitaminB3 compounds (e.g., niacinamide, nicotinic acid and nicotinic acid saltsand esters, including non-vasodilating esters of nicotinic acid (such astocopheryl nicotinate), nicotinyl amino acids, nicotinyl alcohol estersof carboxylic acids, nicotinic acid N-oxide and niacinamide N-oxide),vitamin B5 and retinoids (e.g., retinol, retinal, retinoic acid, retinylacetate, retinyl palmitate, retinyl ascorbate) skin barrier formingagents, melatonin and derivatives, esters, salts and mixtures thereof.

In an embodiment, the active agent is an antidandruff agent. Suitableantidandruff agents include but are not limited to aminexil,benzalkonium chloride, benzethonium chloride,3-bromo-1-chloro-5,5-dimethyl-hydantoin, chloramine B, chloramine T,chlorhexidine, N-chlorosuccinimide, climbazole-,1,3-dibromo-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethyl-hydantoin,betulinic acid, betulonic acid, celastrol, crataegolic acid, cromakalin,cyproterone acetate, dutasteride, finesteride, ibuprofen, ketoconozole,oleanolic acid, phenyloin, picrotone olamine, salicylic acid, seleniumsulphides, triclosan, triiodothyronine, ursolic acid, zinc gluconate,zinc omadine, zinc pyrithione and derivatives, esters, salts andmixtures thereof.

In an embodiment, the active agent is an antihistamine. Suitableantihistamines include but are not limited to chlorcyclizine,diphenhydramine, mepyramine, methapyrilene, tripelennamine andderivatives, esters, salts and mixtures thereof.

In the context, an antibiotic agent is a substance, that has thecapacity to inhibit the growth of or to destroy bacteria and othermicroorganisms. In one or more embodiments, the antibiotic agent isselected from the classes consisting beta-lactam antibiotics,aminoglycosides, ansa-type antibiotics, anthraquinones, antibioticazoles, antibiotic glycopeptides, macrolides, antibiotic nucleosides,antibiotic peptides, antibiotic polyenes, antibiotic polyethers,quinolones, antibiotic steroids, sulfonamides, tetracycline,dicarboxylic acids, antibiotic metals including antibiotic metal ions,oxidizing agents, a periodate, a hypochlorite, a permanganate,substances that release free radicals and/or active oxygen, cationicantimicrobial agents, quaternary ammonium compounds, biguanides,triguanides, bisbiguanides and analogs and polymers thereof, naturallyoccurring antibiotic compounds, including antibiotic plant oils andantibiotic plant extracts, non-classified antibiotic compounds andantibiotic analogs, derivatives, salts, ions, complexes and mixturesthereof.

In an embodiment, the active agent is an antimycotic Also termedantifungal agent. The terms “antimycotic” and “antifungal” as usedherein include, but is not limited to, any substance being destructiveto or inhibiting the growth of fungi and yeast or any substance havingthe capacity to inhibit the growth of or to destroy fungi and/or yeast.

In one or more embodiments, the antifungal agent is an agent that isuseful in the treatment of a superficial fungal infection of the skin,dermatophytosis, microsporum, trichophyton and epidermophytoninfections, candidiasis, oral candidiasis (thrush), candidiasis of theskin and genital mucous membrane, candida paronychia, which inflicts thenail and nail bed and genital and vaginal candida, which inflictgenitalia and the vagina.

Suitable antimycotics include but are not limited to allylamines,amorolfine, amphotericin B, azole compounds, bifonazole, butoconazole,chloroxine, clotrimazole, ciclopirox olamine, clotrimazole, econazole,elubiol, fenticonazole, fluconazole, flucytosine (5FC), griseofulvin,itraconazole, ketoconazole, mafenide acetate, miconazole, naftifine,natamycin, tolnaftate, nystatin, polyenes, oxiconazole, sulbentine,sulconazole, terbinafine, terconazole, tioconazole, undecylenic acid andderivatives, esters, salts and mixtures thereof.

In an embodiment, the active agent is an antipruritic. Suitableantipruritics include but are not limited to menthol, methdilazine,trimeprazine, urea and derivatives, esters, salts and mixtures thereof.

In an embodiment, the active agent is an additional antipsoriatic agent.Suitable additional antipsoriatic agents include but are not limited to6-aminonicotinamide, 6-aminonicotinic acid, 2-aminopyrazinamide,anthralin, 6-carbamoylnicotinamide, 6-chloronicotinamide,2-carbamoylpyrazinamide, corticosteroids, 6-dimethylaminonicotinamide,dithranol, 6-formylaminonicotinamide, 6-hydroxy nicotinic acid,6-substituted nicotinamides, 6-substituted nicotinic acid, 2-substitutedpyrazinamide, tazarotene, thionicotinamide, trichothecene mycotoxins andderivatives, esters, salts and mixtures thereof.

In an embodiment, the active agent is an antirosacea agent. Suitableantirosacea agents include but are not limited to azelaic acid,metronidazole, sulfacetamide and derivatives, esters, salts and mixturesthereof. Certain nonsteroidal anti-inflammatory agents, such assalicylic acid, salicylates, piroxicam and diclofenac are also usefulfor the treatment of Rosacea.

In an embodiment, the active agent is an antiseborrheic agent. Suitableantiseborrheic agents include but are not limited to glycolic acid,salicylic acid, selenium sulfide, zinc pyrithione, a dicarboxylic acid,such as azelaic acid and derivatives, esters, salts and mixturesthereof.

In an embodiment, the active agent is an antiviral agent. Suitableantiviral agents include but are not limited to acyclovir, gancyclovir,ribavirin, amantadine, rimantadine nucleoside-analog reversetranscriptase inhibitors, such as zidovudine, didanosine, zalcitabine,tavudine, lamivudine and vidarabine, non-nucleoside reversetranscriptase inhibitors, such as nevirapine and delavirdine, proteaseinhibitors, such as saquinavir, ritonavir, indinavir and nelfinavir, andinterferons and derivatives, esters, salts and mixtures thereof.

In an embodiment, the active agent is a chemotherapeutic agent. Suitablechemotherapeutic agents include but are not limited to daunorubicin,doxorubicin, idarubicin, amrubicin, pirarubicin, epirubicin,mitoxantrone, etoposide, teniposide, vinblastine, vincristine, mitomycinC, 5-FU, paclitaxel, docetaxel, actinomycin D, colchicine, topotecan,irinotecan, gemcitabine cyclosporin, verapamil, valspodor, probenecid,MK571, GF120918, LY335979, biricodar, terfenadine, quinidine,pervilleine A, XR9576 and derivatives, esters, salts and mixturesthereof.

In an embodiment, the active agent is a corticosteroid. Suitablecorticosteroids include but are not limited to alclometasonedipropionate, amcinafel, amcinafide, amcinonide, beclomethasone,beclomethasone dipropionate, betamethsone, betamethasone benzoate,betamethasone dexamethasone-phosphate, dipropionate, betamethasonevalerate, budesonide, chloroprednisone, chlorprednisone acetate,clescinolone, clobetasol, clobetasol propionate, clobetasol valerate,clobetasone, clobetasone butyrate, clocortelone, cortisone, cortodoxone,craposone butyrate, desonide, desoxymethasone, dexamethasone,desoxycorticosterone acetate, dichlorisone, diflorasone diacetate,diflucortolone valerate, difluorosone diacetate, diflurprednate,fluadrenolone, flucetonide, flucloronide, fluclorolone acetonide,flucortine butylesters, fludroxycortide, fludrocortisone, flumethasone,flumethasone pivalate, flumethasone pivalate, flunisolide, fluocinolone,fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone,fluorometholone, fluosinolone acetonide, fluperolone, fluprednideneacetate, fluprednisolone hydrocortamate, fluradrenolone, fluradrenoloneacetonide, flurandrenolone, fluticasone, halcinonide, halobetasol,hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate,hydrocortisone cyclopentylpropionate, hydrocortisone valerate,hydroxyltriamcinolone, medrysone, meprednisone, .alpha.-methyldexamethasone, methylprednisolone, methylprednisolone acetate,mometasone furoate, paramethasone, prednisolone, prednisone,pregnenolone, progesterone, spironolactone, triamcinolone, triamcinoloneacetonide and derivatives, esters, salts and mixtures thereof.

In an embodiment, the active agent is a hair growth regulator. Suitablehair growth regulators include but are not limited toN-acetylgalactosamine, N-acetylglucosamine, N-acetylmannosamine,acitretin, aminexil, ascomycin, asiatic acid, azelaic acid, benzalkoniumchloride, benzethonium chloride, benzydamine, benzyl nicotinate, benzoylperoxide, benzyl peroxide, betulinic acid, betulonic acid, calciumpantothenate, celastrol, cepharanthine, chlorpheniramine maleate,clindamycin hydrochloride, crataegolic acid, cromakalin, cyproteroneacetate, diazoxide, diphenhydramine hydrochloride, dutasteride,estradiol, ethyl-2-hydroxypropanoate, finasteride, D-fucono-1,5-lactone,furoate, L-galactono-1,4-lactone, D-galactosamine,D-glucaro-1,4-lactone, D-glucosamine-3-sulphate, hinokitiol,hydrocortisone, 2-hydroxypropionic acid, isotretinoin, itraconazole,ketoconazole, latanoprost, 2-methyl propan-2-ol, minocyclin, minoxidil,mipirocin, mometasone, oleanolic acid, panthenol, 1,10-phenanthroline,phenyloin, prednisolone, progesterone, propan-2-ol, pseudoterins,resorcinol, selenium sulfide, tazarotene, triclocarbon, triclosan,triiodothyronine, ursolic acid, zinc pyrithione and derivatives, esters,salts and mixtures thereof.

In an embodiment, the active agent is a hormone. Suitable hormonesinclude but are not limited to methyltestosterone, androsterone,androsterone acetate, androsterone propionate, androsterone benzoate,androsteronediol, androsteronediol-3-acetate,androsteronediol-17-acetate, androsteronediol 3-17-diacetate,androsteronediol-17-benzoate, androsteronedione, androstenedione,androstenediol, dehydroepiandrosterone, sodium dehydroepiandrosteronesulfate, dromostanolone, dromostanolone propionate, ethylestrenol,fluoxymesterone, nandrolone phenpropionate, nandrolone decanoate,nandrolone furylpropionate, nandrolone cyclohexane-propionate,nandrolone benzoate, nandrolone cyclohexanecarboxylate,androsteronediol-3-acetate-1-7-benzoate, oxandrolone, oxymetholone,stanozolol, testosterone, testosterone decanoate, 4-dihydrotestosterone,5a-dihydrotestosterone, testolactone, 17a-methyl-19-nortestosterone,desogestrel, dydrogesterone, ethynodiol diacetate, medroxyprogesterone,levonorgestrel, medroxyprogesterone acetate, hydroxyprogesteronecaproate, norethindrone, norethindrone acetate, norethynodrel,allylestrenol, 19-nortestosterone, lynoestrenol, quingestanol acetate,medrogestone, norgestrienone, dimethisterone, ethisterone, cyproteroneacetate, chlormadinone acetate, megestrol acetate, norgestimate,norgestrel, desogrestrel, trimegestone, gestodene, nomegestrol acetate,progesterone, 5a-pregnan-3b,20a-diol sulfate, 5a-pregnan-3b,20b-diolsulfate, 5a-pregnan-3b-ol-20-one, 16,5a-pregnen-3b-ol-20-one,4-pregnen-20b-ol-3-one-20-sulfate, acetoxypregnenolone, anagestoneacetate, cyproterone, dihydrogesterone, fluorogestone acetate,gestadene, hydroxyprogesterone acetate, hydroxymethylprogesterone,hydroxymethyl progesterone acetate, 3-ketodesogestrel, megestrol,melengestrol acetate, norethisterone, progestins and derivatives,esters, salts and mixtures thereof.

In an embodiment, the active agent is a hydroxy acid. Suitable hydroxyacids include but are not limited to agaricic acid, aleuritic acid,allaric acid, altraric acid, arabiraric acid, ascorbic acid, atrolacticacid, benzilic acid, citramalic acid, citric acid, dihydroxytartaricacid, erythraric acid, galactaric acid, galacturonic acid, glucaricacid, glucuronic acid, glyceric acid, glycolic acid, gularic acid,gulonic acid, hydroxypyruvic acid, idaric acid, isocitric acid, lacticacid, lyxaric acid, malic acid, mandelic acid, mannaric acid,methyllactic acid, mucic acid, phenyllacetic acid, pyruvic acid, quinicacid, ribaric acid, ribonic acid, saccharic acid, talaric acid, tartaricacid, tartronic acid, threaric acid, tropic acid, uronic acids, xylaricacid and derivatives, esters, salts and mixtures thereof.

In an embodiment, the active agent is a keratolytic agent. The term“keratolytic agent” is used herein to mean a compound which loosens andremoves the stratum corneum of the skin, or alters the structure of thekeratin layers of skin. Keratolytic agents are used in the treatment ofmany dermatological disorders, which involve dry skin,hyperkeratinization (such as psoriasis), skin itching (such as xerosis),acne and rosacea. Suitable keratolytic agents include but are notlimited to N-acetylcysteine, azelaic acid, cresols, dihydroxy benzenecompounds, such as resorcinol and hydroquinone, alpha-hydroxy acids,such as lactic acid and glycolic acid, phenol, pyruvic acid, resorcinol,sulfur, salicylic acid, retinoic acid, isoretinoic acid, retinol,retinal, urea and derivatives, esters, salts and mixtures thereof.

In an embodiment, the active agent is a lactam. Suitable lactams includebut are not limited to L-galactono-1,4-lactam, L-arabino-1,5-lactam,D-fucono-1,5-lactam, D-glucaro-1,4-lactam, D-glucurono-6,3-lactam,2,5-tri-O-acetyl-D-glucurono-6,3-lactam,2-acetamido-2-deoxyglucono-1,5-lactam,2-acetamido-2-deoxygalactono-1,5-lactam, D-glucaro-1,4:6,3-dilactam-,L-idaro-1,5-lactam, 2,3,5,tri-O-acetyl-D-glucaro-1,4-lactam,2,5-di-O-acetyl-D-glucaro-1,4:6,3-dilactam, D-glucaro-1,5-lactam methylester, 2-propionoamide-2-deoxyglucaro-1,5-lactam and derivatives,esters, salts and mixtures thereof.

In an embodiment, the active agent is a non-steroidal anti-inflammatoryagent. Suitable non-steroidal anti-inflammatory agent include but arenot limited to azelaic acid, oxicams, piroxicam, isoxicam, tenoxicam,sudoxicam, CP-14,304, salicylates, aspirin, disalcid, benorylate,trilisate, safapryn, solprin, diflunisal, fendosal, acetic acidderivatives, diclofenac, fenclofenac, indomethacin, sulindac, tolmetin,isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac,zomepirac, clindanac, oxepinac, felbinac, ketorolac, fenamates,mefenamic, meclofenamic, flufenamic, niflumic, tolfenamic acids,propionic acid derivatives, ibuprofen, naproxen, benoxaprofen,flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen,carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen,alminoprofen, tiaprofen, pyrazoles, phenylbutazone, oxyphenbutazone,feprazone, azapropazone, trimethazone and derivatives, esters, salts andmixtures thereof.

In an embodiment, the active agent is insecticide. The term“insecticide, is used herein to mean a compound which kills, inhibitsthe growth of, impeded the proliferation of or repels insects.Insecticides include, for example, agents that can kill lice, flees,ticks, mites, scabies and mosquitoes, as well as agents that repel suchinsects. Suitable insecticides include but are not limited to DDT,lindane, malathion, permethrin, allethrin, biopermethrin,transpermethrin, phenothrin, diethyl-m-toluamide, dimethyl phthalate,piperonyl butoxide, pyrethroids and derivatives, esters, salts andmixtures thereof.

In an embodiment, the active agent is a vasodilator. Suitablevasodilators include but are not limited to agents that modulate theactivity of the enzyme nitric oxide synthase, nicotinic acid, ethylnicotinate, amyl nitrite, amyl nitrate, ethyl nitrite, butyl nitrite,isobutyl nitrite, glyceryl trinitrate, octyl nitrite, sodium nitrite,sodium nitroprusside, clonitrate, erythrityl tetranitrate, isosorbidemononitrate, isosorbide dinitrate, mannitol hexanitrate, pentaerythritoltetranitrate, penetrinitol, triethanolamine trinitrate, troInitratephosphate (triethanolamine trinitrate diphosphate), propatylnitrate,nitrite esters of sugars, nitrite esters of polyols, nitrate esters ofsugars, nitrate esters of polyols, nicorandil, apresoline, diazoxide,hydralazine, hydrochlorothiazide, minoxidil, pentaerythritol,tolazoline, scoparone, a beta-adrenergic blocker, analpha-adrenoreceptor blocker, a prostaglandin, sildenafil, dipyridamole,catecholamine, isoproternol, furosemide, prostaglandin, prostacyclin,enalaprilat, morphine, acepromazine, prazosin (α-blocker), enalapril,Captopril, amlodipine, minoxidil, tadalafil, vardenafil, phenylephrin,etilefein, caffeine, capsaicin, an extract capsicum, achilleamillefolium (Yarrow), allium sativum (garlic), amoracia rusticana(horseradish), berberis vulgaris (barberry), cimicifuga racemosa (blackcohosh), coleus forskholii (coleus), coptis (goldenthread), crataegus(hawthorn), eleutherococcus senticosus (siberian ginseng), ginkgo biloba(ginkgo), melissa officinalis (lemon balm), olea europaea (olive leaf),panax ginseng (Chinese ginseng), petroselinum crispum (parsley),scutellaria baicalensis (baical skullcap), tilia europaea (lindenflower), trigonella foenum-graecum (fenugreek), urtica dioica (nettles),valeriana officinalis (valerian), viburnum (cramp, bark, black haw),veratrum viride (American hellebore), verbena officinalis (vervain),xanthoxylum americanum (prickly ash), zingiber officinale (ginger),rauwolfia serpentina (Indian snakeroot), viscum album, wild yam,sasparilla, licorice, damiana, yucca, saw palmetto, gotu kola (centellaasiatica), yohimbine and salts, hazelnut, brazil nut and walnut, andderivatives, esters, salts and mixtures thereof.

In an embodiment, the active agent is a vasoconstrictor. Suitablevasodilators include but are not limited to ephedrine, epinephrine,phenylephrine, angiotensin, vasopressin; an extract ephedra sinica (mahuang), polygonum bistorta (bistort root), hamamelis virginiana (witchhazel), hydrastis canadensis (goldenseal), lycopus virginicus(bugleweed), aspidosperma quebracho (quebracho blanco), cytisusscoparius (scotch broom) and cypress and derivatives, esters, salts andmixtures thereof.

In an embodiment, the active agent is a retinoid. Suitable retinoidsinclude but are not limited to retinol, retinal, retinoic acid,all-trans retinoic acid, isotretinoin, tazarotene, adapalene,13-cis-retinoic acid, acitretin all-trans beta carotene, alpha carotene,lycopene, 9-cis-beta-carotene, lutein and zeaxanthin.

In an embodiment, the active agent is a vitamin D analog. Suitableretinoids include but are not limited to calcipotriene, cholecalciferol,25-hydroxycholecalciferol, 1α,25-dihydroxycholecalciferol,ergocalciferol, 1α,25-dihydroxyergocalciferol,22,23-dihydroergocalciferol, 1,24,25-trihydroxycholecalciferol,previtamin D₃, tachysterol₃ (also termed tacalciol), isovitamin D₃,dihydrotachysterol₃, (1S)-hydroxycalciol, (24R)-hydroxycalcidiol,25-fluorocalciol, ercalcidiol, ertacalciol, (5E)-isocalciol,22,23-dihydroercalciol, (24S)-methylcalciol,(5E)-(10S)-10,19-dihydroercalciol, (24S)-ethylcalciol and(22E)-(24R)-ethyl-22,23-didehydrocalciol. In a preferred embodiment, thevitamin D analog is calcipotriene, which is useful in the treatment ofpsoriasis.

In an embodiment, the active agent is selected from the group consistingof an immunosuppressants and immunoregulating agents. Suitableimmunosuppressants and immunoregulating agents include but are notlimited to cyclic peptides, such as cyclosporine, tacrolimus,tresperimus, pimecrolimus, sirolimus (rapamycin), verolimus, laflunimus,laquinimod, imiquimod derivatives, esters, salts and mixtures thereof.In one or more embodiments, the immunomodulator is a calcineurinInhibitor.

In an embodiment, the active agent is a wart remover. Suitable wartremovers include but are not limited to imiquimod, podophyllotoxin andderivatives, esters, salts and mixtures thereof.

In an embodiment, the active agent is a photodynamic therapy (PDT)agent. Suitable PDT agents include but are not limited to modifiedporphyrins, chlorins, bacteriochlorins, phthalocyanines,naphthalocyanines, pheophorbides, purpurins, m-THPC, mono-L-aspartylchlorin e6, bacteriochlorins, phthalocyanines, benzoporphyrinderivatives, as well as photosensitiser precursors, such asaminolevulinic acid and derivatives, esters, salts and mixtures thereof.

In an embodiment, the active agent is an antioxidant or a radicalscavenger. Suitable antioxidants and radical scavengers agents includebut are not limited to ascorbic acid, ascorbyl esters of fatty acids,magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbylsorbate, tocopherol, tocopheryl sorbate, tocopheryl acetate, butylatedhydroxy benzoic acid, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylicacid, gallic acid, propyl gallate, uric acid, sorbic acid, lipoic acid,diethylhydroxylamine, amino-guanidine, glutathione, dihydroxy fumaricacid, lycine pidolate, arginine pilolate, nordihydroguaiaretic acid,bioflavonoids, curcumin, lysine, methionine, proline, superoxidedismutase, silymarin, tea extracts, grape skin/seed extracts, melanin,and polyunsaturated oils, containing omega-3 and omega-6 fatty acids(e.g., linoleic and linolenic acid, gamma-linoleic acid,eicosapentaenoic acid and docosahexaenoic acid and derivatives, esters,salts and mixtures thereof.

In an embodiment, the active agent is a self-tanning agent, such asdihydroxyacetone.

In an embodiment, the active agent is an agent, capable of treatinghyperhydrosis. Suitable hyperhydrosis agents include but are not limitedto anticholinergic drugs, boric acid, tannic acid, resorcinol, potassiumpermanganate, formaldehyde, glutaraldehyde, methenamine, a Lewis acid,aluminum chloride, aluminum chlorohydrates, zirconium chlorohydrates,aluminum-zirconium-Glycine (AZG) complex, aluminum hydroxybromide, aglycopyrrolate compound, a 5-alpha-reductase inhibitor, finasteride,epristeride, flutamide, spironolactone, saw palmetto extract,cholestan-3-one, a mono- and dicarboxylic acid having 4 to 18 carbonatoms, botulinum toxin, a 5-HT2C receptor antagonist, a 5-HT2C receptorantagonist, ketanserin, ritanserin, mianserin, mesulergine,cyproheptadine, fluoxetine, mirtazapine, olanzapine and ziprasidone.

In an embodiment, the active agent is a sunscreen agent. Suitablesunscreen agents include but are not limited to titanium dioxide, zincoxide, zirconium oxide, iron oxide, p-aminobenzoic acid and itsderivatives (ethyl, isobutyl, glyceryl esters; p-dimethylaminobenzoicacid); anthranilic acid derivatives (i.e., o-amino-benzoates, methyl,menthyl, phenyl, benzyl, phenylethyl, linalyl, terpinyl, andcyclohexenyl esters); salicylates (amyl, phenyl, octyl, benzyl, menthyl,glyceryl, and di-propyleneglycol esters); cinnamic acid derivatives(menthyl and benzyl esters, a-phenyl cinnamonitrile; butyl cinnamoylpyruvate); dihydroxycinnamic acid derivatives (umbelliferone,methylumbelliferone, methylaceto-umbelliferone); trihydroxy-cinnamicacid derivatives (esculetin, methylesculetin, daphnetin, and theglucosides, esculin and daphnin); hydrocarbons (diphenylbutadiene,stilbene); dibenzalacetone and benzalacetophenone; naphtholsulfonates(sodium salts of 2-naphthol-3,6-disulfonic and of2-naphthol-6,8-disulfonic acids); di-hydroxynaphthoic acid, o- andp-hydroxybiphenyldisulfonates, coumarin derivatives (7-hydroxy,7-methyl, 3-phenyl), diazoles (2-acetyl-3-bromoindazole, phenylbenzoxazole, methyl naphthoxazole, quinine salts (bisulfate, sulfate,chloride, oleate, and tannate); quinoline derivatives(8-hydroxyquinoline salts, 2-phenylquinoline); hydroxy- ormethoxy-substituted benzophenones; uric and violuric acids; tannic acidand its derivatives (e.g., hexaethylether); (butyl carbotol) (6-propylpiperonyl)ether; hydroquinone; benzophenones (oxybenzene, sulisobenzone,dioxybenzone, benzoresorcinol, 2,2′,4,4′-tetrahydroxybenzophenone,2,2′-dihydroxy-4,4′-dimethoxybenzophenone, octabenzone;4-isopropyldibenzoylmethane; butylmethoxydibenzoylmethane; etocrylene;octocrylene; [3-(4′-methylbenzylidene bornan-2-one), terephthalylidenedicamphor sulfonic acid and 4-isopropyl-di-benzoylmethane.

In an embodiment, the active agent is a figure-forming agent and anagent, capable of treating cellulite. Suitable such agents include butare not limited to baldderwack extract, butcher's, broom, cayenne,dandelion, red clover, ginkgo biloba, horse chestnut, witch hazel andborage oil, caffeic acid, nicotinic acid, theophiline andpentoxyphilline and salts and derivatives thereof.

Several disorders of the skin, body cavity or mucosal surface (e.g., themucosa or the cavity of the nose, mouth, eye, ear, vagina or rectum)involve a combination of etiological factors. For example, fungal andbacterial infections and that are inflamed and have symptoms of rednessand/or itching warrant therapy that combines an anti-infective agent andan anti-inflammatory agent. Thus, in several cases, combining at leasttwo active agents that treat different etiological factors results in asynergistic effect and consequently higher success rate of thetreatment.

In certain cases, the composition contains two active agents, where eachof the active agents require a different pH environment in order toremain stable. For example, corticosteroids are typically stable atacidic pH values (they have a maximum stability at a pH of about 4-6)and of vitamin D analogues are typically stable at basic pH values (theyhave a maximum stability at pH values above about 8). In order tocircumvent the problem of instability it is preferred that thecomposition is substantially water-free. The term “substantiallywater-free” is intended to indicate that the composition has a watercontent below about 5%, preferably below about 2%, such as below about1.5%.

Fields of Applications

The foamable carrier is suitable for treating any infected surface. Inone or more embodiments, foamable carrier is suitable for administrationto the skin, a body surface, a body cavity or mucosal surface, e.g., thecavity and/or the mucosa of the nose, mouth, eye, ear, respiratorysystem, vagina or rectum (severally and interchangeably termed herein“target site”).

By selecting a suitable active agent, or a combination of at least twoactive agents, the foamable composition is useful in treating an animalor a human patient having any one of a variety of dermatologicaldisorders, including dermatological pain, dermatological inflammation,acne, acne vulgaris, inflammatory acne, non-inflammatory acne, acnefulminans, nodular papulopustular acne, acne conglobata, dermatitis,bacterial skin infections, fungal skin infections, viral skininfections, parasitic skin infections, skin neoplasia, skin neoplasms,pruritis, cellulitis, acute lymphangitis, lymphadenitis, erysipelas,cutaneous abscesses, necrotizing subcutaneous infections, scalded skinsyndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles,paronychial infections, rashes, erythrasma, impetigo, eethyma, yeastskin infections, warts, molluscum contagiosum, trauma or injury to theskin, post-operative or post-surgical skin conditions, scabies,pediculosis, creeping eruption, eczemas, psoriasis, pityriasis rosea,lichen planus, pityriasis rubra pilaris, edematous, erythema multiforme,erythema nodosum, grannuloma annulare, epidermal necrolysis, sunburn,photosensitivity, pemphigus, bullous pemphigoid, dermatitisherpetiformis, keratosis pilaris, callouses, corns, ichthyosis, skinulcers, ischemic necrosis, miliaria, hyperhidrosis, moles, Kaposi'ssarcoma, melanoma, malignant melanoma, basal cell carcinoma, squamouscell carcinoma, poison ivy, poison oak, contact dermatitis, atopicdermatitis, rosacea, purpura, moniliasis, candidiasis, baldness,alopecia, Behcet's syndrome, cholesteatoma, Dercum disease, ectodermaldysplasia, gustatory sweating, nail patella syndrome, lupus, hives, hairloss, Hailey-Hailey disease, chemical or thermal skin burns,scleroderma, aging skin, wrinkles, sun spots, necrotizing fasciitis,necrotizing myositis, gangrene, scarring, and vitiligo.

Likewise, the foamable composition is suitable for treating a disorderof a body cavity or mucosal surface, e.g., the mucosa of the nose,mouth, eye, ear, respiratory system, vagina or rectum. Non-limitingexamples of such conditions include chlamydia infection, gonorrheainfection, hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV),genital warts, bacterial vaginosis, candidiasis, chancroid, granulomaInguinale, lymphogranloma venereum, mucopurulent cervicitis (MPC),molluscum contagiosum, nongonococcal urethritis (NGU), trichomoniasis,vulvar disorders, vulvodynia, vulvar pain, yeast infection, vulvardystrophy, vulvar intraepithelial neoplasia (VIN), contact dermatitis,pelvic inflammation, endometritis, salpingitis, oophoritis, genitalcancer, cancer of the cervix, cancer of the vulva, cancer of the vagina,vaginal dryness, dyspareunia, anal and rectal disease, analabscess/fistula, anal cancer, anal fissure, anal warts, Crohn's disease,hemorrhoids, anal itch, pruritus ani, fecal incontinence, constipation,polyps of the colon and rectum.

In an embodiment, the composition is useful for the treatment of aninfection. In one or more embodiments, the composition is suitable forthe treatment of an infection, selected from the group of a bacterialinfection, a fungal infection, a yeast infection, a viral infection anda parasitic infection.

In an embodiment, the composition is useful for the treatment of wound,ulcer and burn. This use is particularly important since the compositioncreates a thin, semi-occlusive layer, which coats the damaged tissue,while allowing exudates to be released from the tissue.

The composition is also suitable for administering a hormone to the skinor to a mucosal membrane or to a body cavity, in order to deliver thehormone into the tissue of the target organ, in any disorder thatresponds to treatment with a hormone.

In some embodiments, the target site for administration or delivery ofthe compositions described herein includes, without limitation, theskin, a body cavity, a mucosal surface, the nose, the mouth, the eye,the ear canal, the respiratory system, the vagina and the rectum.

In light of the hygroscopic nature of the composition, it is furthersuitable for the treatment and prevention of post-surgical adhesions.Adhesions are scars that form abnormal connections between tissuesurfaces. Post-surgical adhesion formation is a natural consequence ofsurgery, resulting when tissue repairs itself following incision,cauterization, suturing, or other means of trauma. When comprisingappropriate protective agents, the foam is suitable for the treatment orprevention of post surgical adhesions. The use of foam is particularlyadvantageous because foam can expand in the body cavity and penetrateinto hidden areas that cannot be reached by any other alternative meansof administration.

The compositions may be used as a substitute for ointment-basedformulations when petrolatum is not desirable because it causesdisturbance: too greasy, too occlusive, does not allow exudates to bereleased (like in wound & burn). It can also be used for treatment ofdisorders wherein the cosmetic elegance is an issue, like acne, rosacea(where the active agent requires water free environment, as specifiedabove).

Shakability

‘Shakability’ means that the composition contains some or sufficientflow to allow the composition to be mixed or remixed on shaking. Thatis, it has fluid or semi fluid properties. In some very limited cases itmay still be possible to have a foamable composition which is flowablebut not apparently shakable.

Breakability

A breakable foam is thermally stable or substantially so, yet breaksunder sheer force. The breakable foam is not “quick breaking”, i.e., itdoes not readily collapse upon exposure to body temperature environment.Sheer-force breakability of the foam is clearly advantageous overthermally induced breakability, (due to, for example, the presence ofalcohol) since it allows comfortable application and well directedadministration to the target area.

Chemical Instability and Stability

By chemical instability of one or more active agents is meant that atleast one of the one or more active agents is susceptible to one or moreof inter alia reaction, breakdown, ionization or oxidation or the ratethereof is increased when incorporated into a pharmaceutical or cosmeticcarrier that is non-aqueous or substantially non-aqueous.

Conversely by chemical stability of one or more active agents is meantthat at least one of the one or more active agents is less susceptibleto one or more of inter alia reaction, breakdown, ionization oroxidation or the rate thereof is impeded when incorporated into apharmaceutical or cosmetic carrier that is non-aqueous or substantiallynon-aqueous.

Other foamable compositions are described in: U.S. Publication No.05-0232869, published on Oct. 20, 2005, entitled NONSTEROIDALIMMUNOMODULATING KIT AND COMPOSITION AND USES THEREOF; U.S. PublicationNo. 05-0205086, published on Sep. 22, 2005, entitled RETINOIDIMMUNOMODULATING KIT AND COMPOSITION AND USES THEREOF; U.S. PublicationNo. 06-0018937, published on Jan. 26, 2006, entitled STEROID KIT ANDFOAMABLE COMPOSITION AND USES THEREOF; U.S. Publication No. 05-0271596,published on Dec. 8, 2005, entitled VASOACTIVE KIT AND COMPOSITION ANDUSES THEREOF; U.S. Publication No. 06-0269485, published on Nov. 30,2006, entitled ANTIBIOTIC KIT AND COMPOSITION AND USES THEREOF; U.S.Publication No. 07-0020304, published on Jan. 25, 2007, entitledNON-FLAMMABLE INSECTICIDE COMPOSITION AND USES THEREOF; U.S. PublicationNo. 06-0193789, published on Aug. 31, 2006, entitled FILM FORMINGFOAMABLE COMPOSITION; U.S. Publication No. 2007-0292355 published onDec. 20, 2007 and entitled ANTI-INFECTION AUGMENTATION OF FOAMABLECOMPOSITIONS AND KIT AND USES THEREOF; U.S. Publication No. 2008-0069779and entitled DICARBOXYLIC ACID FOAMABLE VEHICLE AND PHARMACEUTICALCOMPOSITIONS THEREOF; U.S. Publication 20080206159, published on Aug.28, 2008 and entitled COMPOSITIONS WITH MODULATING AGENTS; U.S. patentapplication Ser. No. 11/767,442, filed on Jun. 22, 2007, entitledFOAMABLE COMPOSITIONS AND KITS COMPRISING ONE OR MORE OF A CHANNELAGENT, A CHOLINERGIC AGENT, A NITRIC OXIDE DONOR, AND RELATED AGENTS ANDTHEIR USES; U.S. Publication 2008-0069779, published on Mar. 20, 2008and entitled FOAMABLE VEHICLE AND VITAMIN AND FLAVONOID PHARMACEUTICALCOMPOSITIONS THEREOF, all of which are incorporated herein by referencein their entirety. More particularly any of the active ingredients; thesolvents; the surfactants; foam adjuvants; polymeric agents, penetrationenhancers; preservatives, humectants; moisturizers; and other excipientsas well as the propellants listed therein can be applied herein and areincorporated by reference.

The invention is described with reference to the following examples.This invention is not limited to these examples and experiments. Manyvariations will suggest themselves and are within the full intendedscope of the appended claims.

Methodology

The formulations may be made in the following general way withappropriate adjustments for each formulation as will be appreciated bysomeone skilled in the art. Polymers, if any, are mixed, swelled andsolubilized in the waterless medium, when necessary, with appropriateheat until it forms a clear solution. Stabilizing surfactants addedusually with heat, until a homogeneous mixture is obtained, the mixtureis then allowed to cool. The remainder of the ingredients, are thenadded with mixing until they have dissolved in the medium. The activeagent is usually added at the end once the modulating agent, if present,has been incorporated. For foam the canisters are then filled with theabove waterless formula, sealed and crimped with a valve and pressurizedwith the propellant.

A general procedure for preparing foamable compositions is set out in WO2004/037225, which is incorporated herein in its entirety by reference.

Oily Waterless Foam

1. a) Heat oil to about 65° C. to about 70° C. mixing with ahomogenizer; b) add surfactant(s) under mixing with a homogenizer untilany solids are completely liquefied; c) where applicable, make a premixof heat sensitive ingredients with about a quarter part of silicone atroom temperature and set aside; d) Mix b. well and cool rapidly to aboutbelow about 35° C. by plunging the container into an ice bath whilestirring; e) Add the remaining silicone under mixing to the product ofd. to obtain a homogenous mixture. f) Add polymers, if any, and add c)the premix of sensitive ingredients with moderate mixing at about below30° C.; g) Cool to room temperature quickly.

2. Alternatively, cooling may be carried out slowly with stirring bysimply leaving the container with the contents stirring in a room, whichis at room temperature. Note that whilst cooling at stage f. ispreferred to about below 30° C. before adding sensitive ingredients,such as tetracycline antibiotics, for formulations with less (or nosensitive) ingredients cooling may optionally be to about below 35° C.(or about below 40° C.).

In some cases the API's may be added at step 3 with moderate mixing.

Production Under Vacuum

Optionally, the foamable formulation may be produced under nitrogen andunder vacuum. Whilst the whole process can be carried out under anoxygen free environment, it can be sufficient to apply a vacuum afterheating and mixing all the ingredients to obtain an emulsion orhomogenous liquid. Preferably the production chamber is equipped toapply a vacuum but if not the formulation can be for example placed in adessicator to remove oxygen prior to filing and crimping.

Canisters Filling and Crimping

Each aerosol canister is filled with the pre-foam formulation (“PFF”)and crimped with valve using vacuum crimping machine. The process ofapplying a vacuum will cause most of the oxygen present to beeliminated. Addition of hydrocarbon propellant may without being boundby any theory further help to reduce the likelihood of any remainingoxygen reacting with the active ingredient. It may do so, without beingbound by any theory, by one or more of dissolving in the oil orhydrophobic phase of the formulation, by dissolving to a very limitedextent in the aqueous phase, by competing with some oxygen from theformulation, by diluting out any oxygen, by a tendency of oxygen tooccupy the dead space, and by oxygen occupying part of the space createdby the vacuum being the unfilled volume of the canister or thatremaining oxygen is rendered substantially ineffective in theformulation.

Pressurizing

Propellant Filling

Pressurizing is carried out using a hydrocarbon gas or gas mixture.Canisters are filled and then warmed for 30 seconds in a warm bath at50° C. and well shaken immediately thereafter.

Closure Integrity Test.

Each pressurized canister is subjected to bubble and crimping integritytesting by immersing the canister in a 60° C. water bath for 2 minutes.Canisters are observed for leakage as determined by the generation ofbubbles. Canisters releasing bubbles are rejected.

Tests

By way of non-limiting example the objectives of hardness, collapse timeand freeze-thaw cycle (“FTC”) stability tests are briefly set out belowas would be appreciated by a person of the art.

Hardness

LFRA100 instrument is used to characterize hardness. A probe is insertedinto the test material. The resistance of the material to compression ismeasured by a calibrated load cell and reported in units of grams on thetexture analyzer instrument display. Preferably at least three repeattests are made. The textural characteristics of a dispensed foam canaffect the degree of dermal penetration, efficacy, spreadability andacceptability to the user. The results can also be looked at as anindicator of softness. Note: the foam sample is dispensed into analuminum sample holder and filled to the top of the holder.

Collapse Time

Collapse time (CT) is examined by dispensing a given quantity of foamand photographing sequentially its appearance with time duringincubation at 36° C. It is useful for evaluating foam products, whichmaintain structural stability at skin temperature for at least 1 minute.Foams which are structurally stable on the skin for at least one minuteare termed “short term stable” compositions or foams.

Density

In this procedure, the foam product is dispensed into vessels (includingdishes or tubes) of a known volume and weight. Replicate measurements ofthe mass of foam filling the vessels are made and the density iscalculated. The canister and contents are allowed to reach roomtemperature. Shake the canister to mix the contents and dispense anddiscard 5-10 mL. Then dispense foam into a preweighed tube, filling ituntil excess is extruded. Immediately remove (level off) excess foam atboth ends and weigh the filled tube on the weighing balance.

Viscosity

Viscosity is measured with Brookfield LVDV-II+PRO with spindle SC4-25 atambient temperature and 10, 5 and 1 RPM. Viscosity is usually measuredat 10 RPM. However, at about the apparent upper limit for the spindle of˜>50,000CP, the viscosity at 1 RPM may be measured, although the figuresare of a higher magnitude.

FTC (Freeze Thaw Cycles)

Foam appearance under extreme conditions of repeated heating and coolingis evaluated by cycling through cooling, heating, (first cycle) cooling,heating (second cycle) etc., conditions, commencing with −10° C. (24hours) followed by +40° C. (24 hours) and measuring the appearancefollowing each cycle. The cycle is repeated for up to three times.

Chemical Stability

The amount of active agent present is analyzed in foam expelled fromvarious pressurized canisters containing foam formulations using HPLC.Analysis is carried out at zero time and at appropriate time intervalsthereafter. The canisters are stored in controlled temperatureincubators at one or more of 5 C, at 25 C, at, 40 C and at 50 C. Atappropriate time intervals canisters are removed and the amount ofactive agent in the foam sample is measured.

Visual Stability Tests

Spillability

An objective in designing formulations it to formulate so thecomposition does not lose fluidity, and stays spillable after theincorporation of active agent. Spillability means free moving orrotating of formulation inside the glass bottle upon inversion.

Bubble Size

Foams are made of gas bubbles entrapped in liquid. The bubble size anddistribution reflects in the visual texture and smoothness of the foam.Foam bubbles size is determined by dispensing a foam sample on a glassslide, taking a picture of the foam surface with a digital cameraequipped with a macro lens. The diameter of about 30 bubbles is measuredmanually relatively to calibration standard template. Statisticalparameters such as mean bubble diameter, standard deviation andquartiles are then determined. Measuring diameter may also be undertakenwith image analysis software. The camera used was a Nikon D40X Camera(resolution 10 MP) equipped with Sigma Macro Lens (ref: APO MACRO 150 mmF2.8 EX DG HSM). Pictures obtained are cropped to keep a squared regionof 400 pixels×400 pixels.

Microscope Size:

The light microscope enables observing and measuring particles from fewmillimeters down to one micron. Light microscope is limited by thevisible light wavelength and therefore is useful to measuring size ofparticles above 800 nanometers and practically from 1 micron (1,000nanometers).

Shakability

Shakability represents the degree to which the user is able to feel/hearthe presence of the liquid contents when the filled pressurized canisteris shaken. Shaking is with normal mild force without vigorous shaking orexcessive force. When the user cannot sense the motion of the contentsduring shaking the product may be considered to be non-shakable. Thisproperty may be of particular importance in cases where shaking isrequired for affecting proper dispersion of the contents.

Shakability Scoring:

Shakability Good shakability (conforms to required qualityspecification) 2 Moderate shakability (conforms to required qualityspecification) 1 Not shakable (fails to meet required qualityspecification) but 0 may still be flowable and allow foam formation ofquality Is substantially not able to pass through valve BlockUniformityIntra-Canister Uniformity

1. Representative product containers are collected, sample testsolutions are prepared and the content of the analyte is determinedaccording to standard methods in the art. Variability of content ischaracterized as percent difference or relative standard deviation, asappropriate, according to the number of samples evaluated.

2. The results ascertain variability or uniformity within a givencontainer in content of analytes (primarily active pharmaceuticalingredients, but also preservatives) taken from different parts of apressurized canister drug products

3. Two full canisters were shaken according to product instructions.About 1-3 g of Foam was dispensed from each canister and discarded. Foamsufficient for two replicate sample solution preparations was thendispensed into a glass beaker. This represents the initial sample. Amiddle portion is then dispensed from each canister being about half thecanister contents. This middle dispensed portion may be discarded orcollected for testing purposes, as necessary. Foam sufficient for tworeplicate sample solution preparations was then dispensed into a glassbeaker. This represents the final sample. A small amount of formulationremains in the canister. The foam samples were stirred to remove gas/airbubbles. From both the initial and final foam portions from eachcanister 4 separate sample solutions are prepared and analyzed, 2 fromthe initial portion and 2 from the final portion. The percent differenceis calculated as follows:

$\frac{\begin{matrix}{{{Difference}\mspace{14mu}{between}\mspace{14mu}{content}\mspace{14mu}{determined}\mspace{14mu}{in}\mspace{14mu}{initial}}\&} \\{{final}\mspace{14mu}{portions}}\end{matrix}}{{{{Mean}\mspace{14mu}{of}\mspace{14mu}{content}\mspace{14mu}{of}\mspace{14mu}{initial}}\&}\mspace{14mu}{final}\mspace{14mu}{portions}} \times 100$and the intra canister uniformity evaluated from the results.Stock Compositions

Non-limiting examples of how stock solutions are made up with andwithout API are illustrated. Other stock solutions may be made using thesame methodology by simply varying adding or omitting ingredients aswould be appreciated by one of the ordinary skills in the art.

EXAMPLES

The invention is described with reference to the following examples. Forthe purpose of the Examples below it was sufficient to apply a vacuumonly at the crimping stage although for long term stability preferablyany vacuum should be applied during manufacture as well at a sufficientpressure so that any oxygen remaining in the formulation is virtuallynegligible. This invention is not limited to these examples andexperiments. Many variations will suggest themselves and are within thefull intended scope of the appended claims.

A list of the chemical constituents of the Brand names of some of theingredients, used in some of the formulations appears in below in Table3.

TABLE 3 Ingredient List Ingredients brand name category HLB RHLB heavymineral oil Paraffin oil Emollient 10.5 liquid heavy light mineral oilPionier 2076P Emollient 10.5 capric/caprylic Myritol 318 Emollient 5triglyceride cyclomethicone Dow Corning ® 345 Emollient 7.75 Fluiddimethicone Dow Corning 200 ® Emollient 5 Fluid, 350 cSTcyclohexasiloxane and DOW Corning ® 246 Emollient cyclopentasiloxaneFluid phenyltrimethicone DOW Corning ® 556 Emollient Fluid dimethiconolST - Dimethiconol Emollient 40 cyclotetrasiloxane DOW Corning ® 244Emollient Fluid stearyl dimethicone DOW Corning ® Emollient 2503 WAXoctyl dodecanol eutanol Emollient stearyl alcohol Speziol C18 foamadjuvant 15.5 Pharma cetostearyl alcohol foam adjuvant cetearyl alcoholfoam adjuvant myristyl alcohol foam adjuvant PPG 15 stearyl ethersurfactant triethanolamine cetearyl alcohol and Montanov 68 surfactantcetearyl glucoside C14-C22 alkyl alcohol Montanov L surfactant C12-C20alkyl glucoside PEG 100 stearate Polyoxyl 100 surfactant stearate Mirj59 glycerol monostearate Cutina GMS V PH surfactant 3.8 glycerol oleateMonomuls 90-018 surfactant sorbitan oleate Span 80 4.3 steareth-2 Brij72 surfactant 4.9 sorbitan stearate Span 60 surfactant 4.7 methylglucose TEGO Care PS surfactant 6.6 sesquistearate sucrose stearic acidsufhope SE D-1805 surfactant 5 esters D-1805 sorbitan palmitate Span 40surfactant 6.7 butylated hydroxyl toluene α-tocopherol API and oilcalcipotriol hydrate API clindamycin phosphate API acyclovir API azelaicacid API and modulating agent calcitriol API propane + butane +Propellant isobutene (A-46 or 1681)

Section 1—Silicones Section 1 Part A —Silicone Carriers without API'sExample 1 Slow vs. Rapid Cooling with Heavy MineralOil/Cyclomethicone/Glycerol Monostearate Formulation

Ingredients 01- A 01- B 04- C Procedure (I) Slow cooling (I) Rapidcooling (I) Rapid cooling to 40° C. to 40-45° C. to 30° C. (II) Slow toRT (II) Slow to RT (II) Slow to RT Heavy mineral oil 86.00 86.00 86.00Glycerol monostearate 4.00 4.00 4.00 (GMS) Cyclomethicone 5-NF 10.0010.00 10.00 Total 100.00 100.00 100.00 Propellant 8.00 8.00 8.00 ResultsPFF Viscosity 10 RPM 5678.79 (day 1), 7870.32 (day 1), 4958.94 (day 1)7294.44 (day 6) 7246.46 (day 6) Foam Quality Good Good Excellent Colorwhite white white Odor No odor No odor No odor Shakability good GoodGood Density 0.118 0.105 0.150 Hardness 15.76 14.69 ND

Procedure A (01): Heavy mineral oil was heated to ˜60 C, followed by theaddition of glycerol monostearate until fully dissolved. The mixture wascooled slowly to 40-45° C. Cyclomethicone 5-NF was added with vigorousagitation at 40-45° C. The mixture was cooled to room temperature.

Procedure B (01): Heavy mineral oil was heated to ˜60 C, followed by theaddition of glycerol monostearate until fully dissolved. The mixture wascooled rapidly to 40-45° C. using an ice bath. Cyclomethicone 5-NF wasadded with vigorous agitation at 40-45° C. The mixture was cooled toroom temperature.

Procedure C (04): Heavy mineral oil was heated to ˜60 C, followed by theaddition of glycerol stearate until fully dissolved. The mixture wascooled rapidly to 30° C. using an ice bath. Cyclomethicone 5-NF wasadded with vigorous agitation at 30° C. The mixture was cooled to roomtemperature.

Foam quality was good following procedures A and B. Foam quality offormulation prepared by procedure C (fast cooling to 30° C.) gaveexcellent quality. This finding confirms the importance of fast coolingprocedure during the manufacturing. Unexpectedly the viscosity testingdemonstrated large difference was demonstrated in PFF viscosity onday 1. The PFF produced by slow cooling demonstrated lower initialviscosity. Interestingly the viscosity difference was diminishedfollowing six days at room temperature. The color of the PFF was dullfollowing the slow procedure and bright for the fast procedure. Densitywas slightly higher using the slow procedure. Although cyclomethicone5-NF is considered volatile, its boiling point is 205° C. and noevaporation of cyclomethicone 5-NF was detected which emphasizes itsrole in foam quality.

The effect of cooling may vary depending on the formulation content andpossibly the amount of cooling and that the effect of rapid cooling tobelow about 35° C. or perhaps preferably to below about 30° C. may bemore significant than rapid cooling to about 40-45° C.

Accordingly, in some embodiments, the compositions described herein areprepared by a process that slowly cools the mixture, thereby improvingthe feel of the prefoam formulation. In some embodiments, thecompositions described herein are prepared by a process that rapidlycools the mixture, thereby resulting in a prefoam formulation having ahigher viscosity.

Example 2 Slow vs. Rapid with Light+Heavy Mineral OilMixture/Cyclomethicone 5-NF/Glycerol Monostearate Formulation Effect ofCooling on Manufacture

Ingredients 133--P(A) 133--P(B) Procedure Rapid cooling to 30° C. Slowcooling to RT Heavy mineral oil 25.00 25.00 Light mineral oil 61.0061.00 Glycerol monostearate 4.00 4.00 Cyclomethicone 5-NF 10.00 10.00Total 100.00 100.00 Propellant 8.00 8.00 Results PFF Viscosity (cPi)10765.7 1393.7 Microscopic examination Uniform preparation Uniformpreparation Visual inspection Homogeneous. Non-homogeneous; phaseseparation 10/90 Foam Quality Good Fairly Good Color white white Odor Noodor No odor Shakability good good Density (g/mL) 0.098 0.089Microscopic observation Uniform particles Uniform particles distributiondistribution; Hardness (g) 14.95 12.58 Bubble size (μm) 61 micronstandard 135 Standard deviation = 34 deviation = 113

A batch of formulation 133 was prepared in two different ways, part withslow cooling and part with fast cooling. The fast cooling was achievedby immersing the container into an ice bath with stirring to reach roomtemperature whilst the other part was merely left to cool to roomtemperature with stirring without any external bath.

Procedure A 133-P(A): Mineral oil was heated to ˜60° C., followed by theaddition of glycerol monostearate until full dissolution. The mixturewas cooled rapidly to 30-33° C. using an ice bath, cyclomethicone 5-NFwas added in one portion. The mixture was allowed to reach roomtemperature while stirring.

Procedure B 133-P (B): Mineral oil was heated to ˜60° C., followed byaddition of glycerol monostearate until fully dissolved. The mixture wascooled slowly to room temperature. Cyclomethicone 5-NF was added at30-33° C. while stirring. The mixture was allowed to reach roomtemperature while stirring.

The data demonstrate that, surprisingly, foam quality appears to bebetter when the formulation is subjected to rapid cooling.

Surprisingly it has been observed that the appearance of the pre-foamformulation before addition of propellant is different depending on therate of cooling applied to the formulation at the end of themanufacturing process.

Foam quality was designated as good following the fast cooling procedurein comparison to a fairly good foam following the slow coolingprocedure. The foam was also more stable. Bubble size of foam preparedby fast cooling procedure was smaller in comparison to bubble size ofthe foam prepared by slow cooling procedure.

Example 3 Mode of Cyclomethicone 5-NF Addition to Formulation withLight+Heavy Mineral Oil Mixture/Cyclomethicone 5-NF/GlycerolMonostearate (GMS) Formulation.

Composition 133-P(A) 133-P(C) 133-P(D) 133-P(E) Procedure (I) Instant(I) Instant (I) Instant (I) Instant cooling to cooling to cooling tocooling to 30° C. 27-30° C. 20-25° C. 15-20° C. (II) to RT (II) to RT(II) to RT (II) to RT Light Mineral 25.00 25.00 25.00 25.00 Oil HeavyMineral 59.91 59.91 59.91 59.91 Oil GMS 4.00 4.00 4.00 4.00Cyclomethicone 10.00 10.00 10.00 10.00 5-NF PFF Viscosity (cPi) 10765.711581.53 8318.23 7966.3 Microscopic Uniform Uniform Uniform Uniformobservation preparation preparation preparation preparation VisualHomogenous. Homogenous. Homogenous. Homogenous. inspection Foam QualityGood Excellent Good to Excellent Excellent Color White, White, WhiteWhite Shakability Good Good Good Good Density (g/mL) 0.098 0.075 0.0670.068 Microscopic Uniform Uniform Uniform Uniform observation particlesparticles particles particles distribution distribution distributiondistribution Hardness (g) 14.95 13.03 11.51 13.11 bubble size(μm) 61micron 83 micron 161 micron 96 micron standard standard standardstandard deviation = 34 deviation = 43 deviation = 97 deviation = 60Uniformity of Homogenous Non- Non- Non- formulation in homogenous;homogenous; homogen. pressurized reversible reversible reversible glassbottles

133-P(A): The mixture of light and heavy mineral oils was heated to 60°C., followed by addition of glycerol monostearate until fulldissolution. The mixture was cooled rapidly to 30° C. using an ice bath.Cyclomethicone 5-NF was added in one portion at 30° C. while stirring.The mixture was allowed to reach room temperature while stirring.

133-P(C): The mixture of light and heavy mineral oils was heated to 60°C. ¾ of cyclomethicone 5-NF amount was added while stirring at 60° C.,followed by addition of glycerol monostearate until full dissolution.The mixture was cooled rapidly to 27-30° C. using an ice bath. Quarter(¼) of total cyclomethicone 5-NF amount was added at 27-30° C. whilestirring. The mixture was allowed to reach room temperature whilestirring.

133-P(D): The mixture of light and heavy mineral oils was heated to 60°C., followed by addition of glycerol monostearate until fulldissolution. The mixture was cooled rapidly to 20-25° C. using an icebath. Cyclomethicone 5-NF was added in one portion at 23° C. whilestirring. The mixture was allowed to reach room temperature whilestirring.

133-P(E): The mixture of light and heavy mineral oils was heated to 60°C., followed by addition of glycerol monostearate until fulldissolution. The mixture was cooled rapidly to 15-20° C. using an icebath. Cyclomethicone 5-NF was added in one portion at 18° C. whilestirring. The mixture was allowed to reach room temperature whilestirring.

Addition of cyclomethicone 5-NF in two portions improved the foamquality from good to excellent. Fast cooling of mineral oils andglycerol monostearate mixture to lower temperature 15-20° C. compared to30° C. improved foam quality. Addition of cyclomethicone 5-NF in oneportion cause the formulation to be homogenous however, non-homogeneitythat was observed in formulations 133-P(c), 133-P(D) and 133-P(E) wasreversible by inversion of the bottle.

This data confirms the importance of fast cooling procedure and verifiesthat when cyclomethicone is added at lower temperature, the foam qualityis higher.

Example 4 Various Concentrations of Cyclomethicone 5-NF with HeavyMineral Oil Mixture/Cyclomethicone 5-NF/Glycerol MonostearateFormulation

Ingredients 014 06 07 Procedure (I) Instant cooling to 30° C. (II) to RTHeavy mineral oil 91.00 76.00 66.00 Glycerol 4.00 4.00 4.00 monostearateCyclomethicone 5- 5.00 20.00 30.00 NF Ratio GMS:CM 4:5 1:5 2:14 Total100.00 100.00 100.00 Propellant 8.00 8.00 8.00 Results PFF Viscosity 10RPM 7022 5166 5342 Foam Quality Good Fairly Good Fairly Good Color WhiteWhite White Odor No odor No odor No odor Shakability Good Good GoodDensity 0.157 0.136 0.115 Hardness 21.78 8.78 9.26

Heavy mineral oil was heated to —60° C., followed by the addition ofglycerol monostearate until fully dissolved. The mixture was cooledrapidly to 30° C. using an ice bath. Cyclomethicone 5-NF was added withvigorous agitation at 30° C. The mixture was cooled to room temperature.

Foam quality was reduced from Good to fairly good by using higherconcentration of cyclomethicone without changing the concentration ofglycerol monostearate (see the formulations 014, 06 and 07). Foamquality of formulation 06 was significantly improved by addition ofglycerol monostearate.

Hardness of the foam was reduced when higher percentage ofcyclomethicone 5-NF was used.

In the above mentioned formulations, 014, 006, 007, high concentrationsof cyclomethicone 5-NF result in low foam quality. Therefore thequestion posed was whether the GMS/CM ratio is of importance to the foamquality.

Example 5 Comparative Studies of Silicone Compounds Heavy Mineral OilMixture/Glycerol Monostearate Formulation

Ingredients 20 21 022 035- 023 024 025 Procedure Instant cooling to 30°C. Heavy mineral oil 86.00 86.00 86.00 86.00 86.00 86.00 86.00 Glycerol4.00 4.00 4.00 4.00 4.00 4.00 4.00 monostearate Dow Corning 246 10.00fluid (d5 + d6) Dimethiconol 10.00 Dimethicone 1.5 10.00 Dimethicone 35010.00 Phenyltrimethicone 10.00 Dow Corning 244 10.00 cyclotetrasiloxaneStearyl dimethicone 10.00 Total 100.00 100.00 100.00 100.00 100.00100.00 100.00 Propellant 8.00 8.00 8.00 8.00 8.00 8.00 8.00 Results PFFViscosity 10 RPM 8782 4191 1762 914.81 7390 2397.49 5118.91 Foam QualityGood Good Fairly Good Fairly Good Good Good Excellent Color White WhiteWhite White White White White Odor No odor No odor No odor No odor Noodor No odor No odor Shakability Good Good Good Good Good Good GoodDensity 0.158 0.175 Not tested Not tested 0.202 0.198 0.214 due tofairly due to fairly good foam good foam quality quality Hardness 15.6513.50 Not tested Not tested 16.58 20.48 29.65 due to fairly due tofairly good foam good foam quality quality

Heavy mineral oil was heated to ˜60° C., followed by the addition ofglycerol stearate until full dissolution. The mixture was cooled rapidlyto 30° C. using an ice bath. Siloxane compounds were added with vigorousagitation at 30° C. The mixture was brought to room temperature whilestirring.

TABLE 4 Comparison of different silicones (incorporated in the same baseformulation in the same amount) and resultant foam properties ViscosityFoam See Siloxane (cPi) Structure volatility Quality Example Dow corning246 Fluid (d6 + d5) 6.8 cyclic + Good 21 (cyclohexasiloxane &cyclopentasiloxane) Dimethiconol 41 linear Good 21 Dimethicone 1.5 1.5linear + Fairly Good 21 Dimethicone 350 350 linear Fairly Good 1Phenyltrimethicone 22.5 linear Good 21 Dow Corning 244 Fluid 2.4cyclic + Good 21 (cyclotetrasiloxane) Stearyl dimethicone 40 (at linearGood 21 40° C.) Cyclomethicone 5-NF 4 cyclic + Good - 1 Excellent

Without being bound to any theory, the quality of foam consisting ofmineral oil, glycerol monostearate and silicones, relates to the spatialstructure of silicones used. When cooled rapidly, Mineral oil andglycerol monostearate create a stable structure. Silicones such asCyclomethicone 5-NF, Dow Corning 244 Fluid, and Dow corning 246 Fluidall posses a cyclic structure. This cyclic structure may deprive themfrom penetrating in between the mineral oil/GMS structure, therefore itis thought that perhaps they do not affect the stability of mineraloil/GMS structure in a substantial way. Using such cyclic siliconestherefore results in a high quality foam.

Linear silicones such as Dimethicone 1.5 and Dimethicone 350 have ahydrophobic chain-like structure. Since they may be capable of formingVan Der Waals interactions with the Glycerol monostearate/oil, it isthought—without being bound by any theory—that they are trapped betweenthe hydrophobic chains of mineral oil. This may cause destabilization ofhydrophobic-hydrophobic interactions between mineral oil chains andGlycerol monostearate, and thus decreases formulation stability. Theresult is a reduced foam quality, such as fairly good.

However, other linear silicones such as Phenyltrimethicone, Dimethiconoland stearyl dimethicone which consist of large structural moieties, maycause stearic hindrance and therefore, may be unable to destabilize themineral oil/glycerol monostearate structure. The followingmechanisms—without being bound by any theory—are suggested to explainthis phenomenon:

1. Phenyl trimethicone has a benzyl ring and three methyl groups thatcreate a structure which may not be able to penetrate in between themineral oil/GMS and may not cause substantial destabilization.

2. Dimethiconol which has OH groups may not interact with the mineraloil significantly since it would create a repelling effect. Due to thiseffect dimethiconol may not penetrate in between the mineraloil/glycerol monostearate structure and destabilize it.

3. Stearyl dimethicone acts in the similar way to phenyl trimethicone informulation due to its long linear aliphatic chains.

Example 6 Impact of Ratios of Glycerol Monostearate and Cyclomethicone5-NF on Formulation Properties

Ingredients 036 033 06 Procedure (I) Instant cooling to 30° C. (II) toRT Heavy mineral oil 79.00 71.00 76.00 Glycerol 6.00 9.00 4.00monostearate Cyclomethicone 5- 15.00 20.00 20.00 NF Ratio GMS:CM 4:5 4:51:5 Total 100.00 100.00 100.00 Propellant 8.00 8.00 8.00 Results PFFViscosity 10 RPM 4926.95 8762.8 5166 Foam Quality Good Good Fairly GoodColor White White White Odor No odor No odor No odor Shakability GoodGood Good Density 0.144 0.130 0.136 Hardness 11.09 10.77 8.78

Heavy mineral oil was heated to ˜60 C, followed by the addition ofglycerol monostearate until fully dissolved. The mixture was cooledrapidly to 30° C. using an ice bath. Cyclomethicone 5-NF was added withvigorous agitation at 30° C. The mixture was cooled to room temperaturewhile stirring.

Foam Quality was good when Glycerol monostearate to Cyclomethicone 5-NFratio was 2.5. Apparently the ratio between Glycerol monostearate andcyclomethicone 5-NF plays a role in the foam quality. When the ratio washigher than about 4:5 (e.g. 06 and 07) foam quality was reduced tofairly good. Therefore, in order to maintain good foam, the recommendedratio between Glycerol monostearate and cyclomethicone 5-NF should bepreferably 1:1 to 1:4 by weight.

Section 1 PART B—Silicone Carriers with API's Example 7 Heavy MineralOil, Glycerol Monostearate and Cyclomethicone 5-NF a Volatile Siliconewith Various API's

A) Soluble API's

Ingredients 18A 18B Procedure (I) Rapid cooling to 40-45° C., (II) to RTHeavy Mineral Oil 68.80 85.99 Glycerol monostearate 3.20 4.00Cyclomethicone 5-NF 8.00 10.00 α-Tocopherol 20.00 Calcipotriol 0.01Total 100.00 100.00 Propellant 12.00 12.00 (propane + butane +isobutene) A46 RESULTS PFF¹ Viscosity (10 RPM) 2147.54 5006.93Microscope No Crystals No Crystals FOAM Foam Quality Good Good ColorOff-White White Odor No Odor No Odor Shakability Good Good Density 0.0900.082 Collapse Time (36° c.-Sec.) >300/FG >300/FG Bubble Mean Size (Mm)82.00 118.00 Bubbles Above 500 Mm (%) 0.00 0.00 Microscope No CrystalsNo Crystals FTC Foam Quality Fairly Good Good Color Off-White White OdorNo Odor No Odor Shakability Good Good Microscope No Crystals No Crystals¹Prefoam Formulation

Heavy mineral oil was heated to about 60° C. followed by the addition ofglycerol stearate until fully dissolved. The mixture was cooled rapidlyto about 40-45° C. Cyclomethicone 5-NF was added with vigorous agitationand cooled to room temperature. API was added with stirring.

The combination of heavy mineral oil, glycerol monostearate,cyclomethicone 5-NF, and a-tocopherol or calcipotriol produces a goodstable foam. Formulation B, containing calcipotriol produces a slightlyimproved foam, particular following repeated freeze thaw cycling. Thisimproved foam quality may be due in part to the higher viscosity offormulation B, as tocopherol is an oil.

B) Suspended API's

Ingredients 18C 18D 18E Procedure (I) Rapid cooling to 40-45° C., (II)RT Heavy Mineral Oil 84.28 81.70 73.10 Glycerol monostearate (GM) 3.923.80 3.40 Cyclomethicone 5-NF 9.80 9.50 8.50 Clindamycin Phosphate 2.00Acyclovir 5.00 Azelaic acid 15.00 Total 100.00 100.00 100.00Propellant(propane + 12.00 12.00 12.00 butane + isobutene) A46 RESULTSPFF Viscosity (10 RPM) 767.84 1069.77 12957.23 Microscope CrystalsCrystals Crystals FOAM Foam quality Good Good Good Color White WhiteWhite Odor No odor No odor No odor Shakability Good Good ModerateDensity 0.103 0.097 0.108 Collapse Time (36C.-Sec.) >300/FG >300/FG >300/FG Bubble Mean Size (Mm) 89.00 124.00168.00 Bubbles Above 500 Mm (%) 0.00 0.00 0.00 Microscope Crystals,Crystals, Crystals, Uniform Uniform Uniform Dispersion DispersionDispersion FTC Foam quality Good Good Fairly Good Color White WhiteWhite Odor No Odor No Odor No Odor Shakability Good Good Good MicroscopeCrystals, Crystals, Crystals, Uniform Uniform Uniform DispersionDispersion Dispersion

The combination of mineral oil, glycerol monostearate and cyclomethicone5-NF produces good stable foam that is not adversely effected by one ormore of API, its concentration and its solubility in oil (for example,α-tocopherol is soluble in oil, whereas clindamycin phosphate issuspended).

Example 9 Heavy Mineral Oil, Glycerol Monostearate and Dimethicone 350cst, a Non-Volatile Silicone with Various API's

A) Soluble API's

Ingredients 19A 19B Procedure (I) Rapid cooling to 35-40° C., (II) to RTHeavy Mineral Oil 68.80 85.99 Glycerol monostearate 3.20 4.00Dimethicone (350 cst) 8.00 9.99 α-tocopherol 20.00 Calcipotriol hydrate0.01 Total 100.00 100.00 Propellant(propane + 12.00 12.00 butane +isobutene) A46 RESULTS PFF Viscosity (10 RPM) 595.87 1302.72 Foam FoamQuality Fair Fair Color Off-White White Odor No Odor No Odor ShakabilityGood Good

Heavy mineral oil was heated to about 50-55° C. followed by the additionof glycerol stearate until fully dissolved. The mixture was cooledrapidly to about 35-40° C. Dimethicone 350 was added with vigorousagitation and cooled to room temperature. API was added with stirring.

Comparison of 19A with 18A of Example 1 and comparison of Example 19Bwith 18B of Example 1, discloses that unexpectedly the volatile siliconecyclomethicone 5-NF produces foam of a higher quality than similaramounts of its non-volatile counterpart dimethicone.

B) Suspensed API's

Ingredients 19C 19D 19E Procedure (I) Rapid cooling to 35-40° C., (II)to RT Heavy Mineral Oil 84.28 81.70 73.10 Glycerol monostearate 3.923.80 3.40 Dimethicone 350 9.80 9.50 8.50 Clindamycin Phosphate 2.00Acyclovir 5.00 Azelaic acid 15.00 Total 100.00 100.00 100.00Propellant(propane + 12.00 12.00 12.00 butane + isobutene) A46 RESULTSPFF Viscosity (10 RPM) 953.8 1312.72 11053.64 Foam Foam Quality FairFairly Fairly Good Good Color White White White Odor No Odor No Odor NoOdor Shakability Good Good Good

Parallel formulations to those seen in Example 1 were prepared with anon-volatile silicone. In all the examples in A and B the foam qualitywas substantially reduced. Likewise, comparison of 19C with 18C ofExample 1 and comparison of Example 19D with 18D of Example 1, andcomparison of Example 19E with 18E of Example 1, also discloses thatunexpectedly the volatile silicone cyclomethicone 5-NF produces foam ofa higher quality than similar amounts of its non-volatile counterpartdimethicone. Thus, dimethicone 350 (a non-volatile silicone) may beacting as a stronger defoamer.

Example 10 Comparison Between a Formulation with a Volatile Silicone andPartial Rapid Cooling to 40-45° C. and a Formulation with a Combinationof 2 Silicones One of which is Volatile with Slow Cooling

Ingredients 23E 18E Procedure (I) Slow cooling to 30- (I) Rapid coolingto 40- 35° C., (II) Slow to RT 45° C., (II) Slow to RT Heavy Mineral Oil61.00 73.10 Glycerol monostearate 4.00 3.40 Dimethicone (350 cst) 10.00Cyclomethicone 5-NF 10.00 8.50 Azelaic acid 15.00 15.00 Total 100.00100.00 Propellant(propane + 12.00 12.00 butane + isobutene) A46 RESULTSPFF Viscosity (10 RPM) 8014.29 12957.23 Foam Foam Quality Fair GoodColor White White Odor No Odor No Odor Shakability Good Good

Procedure for 18E—see Example 1

Procedure for 23E—Heavy mineral oil was heated to about 50-55° C.followed by the addition of glycerol monostearate until fully dissolved.The mixture was cooled to about 30-35° C. Cyclomethicone 5-NF was addedwith vigorous agitation and cooled to room temperature. Azelaic acid wasadded with stirring.

Adding a non-volatile silicone (dimethicone 350) to a volatile(cyclomethicone) silicone results in a significant reduction in foamquality, which in part may possibly be attributed to the slow cooling.Thus, the negative defoaming character of the non-volatile siliconedimethicone 350 overrides the positive unexpected foaming effect of thevolatile cyclic silicone cyclomethicone.

Section 2—Surfactants

See above Example 6 for Study on Impact of Ratio of GlycerolMonostearate and Cyclomethicone 5-NF

This study demonstrates the preferred ratio between Glycerolmonostearate and cyclomethicone should be preferably 4:5 to 1:4 byweight.

Example 11 Comparison Between a Surfactant Glycerol Monostearate and aFoam Adjuvant Stearyl Alcohol with Heavy Mineral Oil in the Presence ofCyclomethicone 5-NF

Ingredients 21C 18C Procedure (I) Rapid cooling (I) Rapid cooling to 40-45° C., to 40-45° C., (II) Rapid to RT (II) RT Heavy Mineral Oil 84.2884.28 Glycerol monostearate 3.92 Stearyl alcohol 3.92 Cyclomethicone5-NF 9.80 9.80 Clindamycin Phosphate 2.00 2.00 Total 100.00 100.00Propellant(propane + 12.00 12.00 butane + isobutene) A46 RESULTS PFFViscosity (10 RPM) 110.98 767.84 Foam Foam Quality Fair Good Color WhiteWhite Odor No Odor No Odor Shakability Good Good Density N/M 0.103Collapse Time (36 C.-Sec.) N/M >300/FG Bubble Mean Size (Mm) N/M 89.00Bubbles Above 500 Mm (%) N/M 0.00 N/M = Not measured

Replacing glycerol monostearate with stearyl alcohol (which is a wax,but not a surfactant) results in a significant reduction in foamquality. Thus foam adjuvant alone without surfactant is not able toproduce quality foam form oil with silicone.

Procedure for 18C—see example 1

Procedure for 21 C: Heavy mineral oil was heated to about 50-55° C.followed by the addition of stearyl alcohol until fully dissolved. Themixture was cooled rapidly to about 40-45° C. Cyclomethicone was addedwith vigorous agitation and cooled rapidly to room temperature.Clindamycin Phosphate was added.

Example 12 Comparison Between Span 80 (a Sorbitan Ester, LiquidSurfactant) and Glycerol Monostearate (Solid Surfactant)

Ingredients 22B 18B Procedure (I) Cooling (I) Rapid cooling to 40-45° C.to 40-45° C. (II) Rapid to RT (II) RT Heavy Mineral Oil 85.99 85.99 Span80 (sorbitan ester) -liquid 3.99 Glycerol monostearate -solid 3.99Cyclomethicone 5-NF 10.00 10.00 Calcipotriol hydrate 0.01 0.01 Total100.00 100.00 Propellant(propane + 12.00 12.00 butane + isobutene) A46RESULTS PFF viscosity (10 RPM) 73.98 5006.93 FOAM Foam quality Fair GoodColor White White Odor No odor No odor Shakability Good Good Density N/M0.082 Collapse time (36 C.-sec.) N/M >300/FG Bubble mean size (μm) N/M118.00 Bubbles above 500 μm (%) N/M 0.00 N/M = Not measured

Procedure: for 18B—see Example 1

Procedure for 22B: Heavy mineral oil was heated to about 50-55° C.followed by the addition of Span80 until fully dissolved. The mixturewas cooled to about 40-45° C. Cyclomethicone 5-NF was added withvigorous agitation and cooled rapidly to room temperature. Calcipotriolhydrate was added with stirring.

Replacing a solid surfactant (glycerol monostearate) with a sorbitanester which is liquid results in a significant reduction in foamquality. Liquid sorbitan esters on their own did not result in foams ofquality.

Example 13 Comparison of Four Surfactants, Two from Glycerol Fatty AcidDerivatives—and Two from Alkyl Alcohol/Alkyl Glucosides

Ingredients 04- C 038 040 039 045 Procedure (I) Rapid (I) Rapid to27-30° C. (II) RT to 30-35° C. (II) RT Heavy Mineral Oil 86.00 86.0086.00 86.00 86.00 Glycerol monostearate 4.00 Glycerol oleate 4.00(Monomuls 90-018) Montanov 68 (cetearyl alcohol and 4.00 cetearylglucosides) Montanov L (C14-C22 Alkylalcohol and 4.00 C12-20Alkylglucoside) Glycerol palmitostearate 4.00 Cyclomethicone 5-NF 10.0010.00 10.00 10.00 10.00 Total 100.00 100.00 100.00 100.00 100.00Propellant(propane + 8.00 8.00 8.00 8.00 8.00 butane + isobutene) A70RESULTS PFF Viscosity (10 RPM) 4958.94 984.79 797.83 486.9 Not testedFoam Foam Quality Excellent Fair Fairly Fairly Excellent good good Colorwhite white white white white Odor No odor No odor No odor No odor Noodor Shakability Good Good Good Good Good Density (g/mL) 0.150 NA NA0.147 0.118 Hardness NA NA 5.37 7.52 Not tested

Mineral oil was heated to ˜60-65° C., followed by the addition ofglycerol stearate, until fully dissolved. The mixture was cooledinstantly to 27-30° C. using an ice bath. Cyclomethicone 5-NF was addedwith vigorous agitation at 30° C. The mixture was cooled to roomtemperature.

Surprisingly, when a surfactant from the same family (glycerides offatty acids)—Glycerol monooleate (Monomuls) was used, the foam qualitywas fairly good namely, it produced a poorer foam structure and was lesseffective than glycerol monostearate which consistently and unexpectedlyproduced foam of at least good quality. Viscosity was reduced incomparison to formulation 040. It may be assumed that the structuraldifference between oleate and stearate plays a role in the foamstability.

When Montanov family (68 and L) glycosides and fatty alcohols wereemployed (Montanov L which contains cocoglucoside and Montanov 68 whichcontains cetearyl alcohol and cetearyl glucoside—a combination ofsurfactant and foam adjuvant), the foam quality was fairly good to goodnamely foam quality was reduced compared to glycerol monostearate.Viscosity was also reduced in comparison to formulation 04-C.Interestingly Glycerol palmitostearate also produced foam of highquality.

Without being bound to any theory, it appears that glycerol monostearateplays a crucial part in the establishment of foam quality ofoil/silicone formulations. This unique success of both glycerolmonostearate and also glycerol palmitostearate alone is quite unexpectedsince it is known that glycerol mono and di stearate and other fattyacid monoesters are not efficient surfactants.

Example 14 Comparison of Fatty Acids Derivative Cetearyl Alcohol

Ingredients 041 Procedure (I) Rapid to 27-30° C. (II) to RT HeavyMineral Oil 86.00 Cetearyl alcohol 4.00 Cyclomethicone 5-NF 10.00 Total100.00 Propellant(propane + 8.00 butane + isobutene) A46 RESULTS PFFViscosity (10 RPM) 768.84 Foam Foam Quality Fairly good Color White OdorNo odor Shakability Good Density 0.168 Hardness 13.07

Mineral oil was heated to ˜60-65° C., followed by the addition ofglycerol stearate, until fully dissolved. The mixture was cooledinstantly to 27-30° C. using an ice bath. Cyclomethicone 5-NF was addedwith vigorous agitation at 30° C. The mixture was cooled to roomtemperature.

This example presents the formulations prepared with fatty acidsderivative Cetearyl alcohol and as foam adjuvant and surfactantrespectively.

It appears that cetearyl alcohol which is a foam adjuvant alone providesfoam of fairly good quality. The viscosity of the PFF was low incomparison to formulation 04.

Example 15 Surfactant Studies Glycerol Monostearate+PEG 100 Stearate

019-081027 Ingredients Heavy mineral oil 86.00 Glycerol monostearate +4.00 PEG 100 stearate Cyclomethicone 5-NF 10.00 Total 100.00 Propellant8.00 Results PFF Viscosity 10 RPM Foam Quality Good Color white Odor Noodor Shakability good Density 0.010 Hardness 9.62 Babble size 84

Procedure: Mineral oil was heated to ˜60° C., followed by the additionof glycerol stearate, until fully dissolved. The mixture was cooledinstantly to 30° C. using an ice bath. Cyclomethicone 5-NF was addedwith vigorous agitation at 30° C. The mixture was cooled to roomtemperature.

Foam quality surprisingly was good using GMS PEG 100 monostearatealthough it is more hydrophilic properties compared to glycerolmonostearate solely. Density was low compared to glycerol monostearatealone.

Example 16 Heavy Mineral Oil, Cyclomethicone 5-NF and Sorbitan EsterSurfactants

A) Solid Span Surfactants

Ingredients 25 28 Procedure (I) Slow to 35-40° C. (II) Slow to RT HeavyMineral Oil 86.00 86.00 Span 60 4.00 Span 40 4.00 Cyclomethicone 5-10.00 10.00 NF Total 100.00 100.00 Propellant (A46 a 12.00 12.00 mixtureof propane, butane and isobutane) RESULTS FOAM Foam Quality Fair FairColor White White Odor No Odor No Odor Shakability Good Good

Formulations with sorbitan ester surfactants alone did not produce foamsof quality.

B) Other Solid Surfactants

Ingredients 24 26 27 Procedure (I) Slow to 35-40° C. (II) Slow to RTHeavy Mineral Oil 86.00 86.00 86.00 steareth-2 4.00 methyl glucosesesquistearate 4.00 sufhope SE D-1805 4.00 Cyclomethicone 5-NF 10.0010.00 10.00 Total 100.00 100.00 100.00 Propellant(propane + butane +12.00 12.00 12.00 isobutene) A46 RESULTS FOAM Foam Quality Fair FairFair Color White White White Odor No Odor No Odor No Odor ShakabilityGood Good Good

Procedure for (24-27): Heavy mineral oil was heated to about 50-55° C.followed by the addition of Surfactant until fully dissolved. Themixture was cooled to about 35-40° C. Cyclomethicone was added withvigorous agitation and cooled to room temperature.

The formulations above demonstrate that not all solid surfactants areappropriate.

Section 3—Oils Example 17 Ratios of Light and Heavy Mineral Oil

Following the results in example 18, studies were performed toinvestigate different ratios of light and heavy mineral oil role informulation

Ingredients 08 09 010 011 Procedure Slow to Instant cooling to 30° C.40° C. Light mineral oil 86.00 86.00 43.00 28.50 Heavy mineral oil 43.0057.50 Glycerol monostearate 4.00 4.00 4.00 4.00 Cyclomethicone 5-NF10.00 10.00 10.00 10.00 Total 100.00 100.00 100.00 100.00 Propellant8.00 8.00 8.00 8.00 Results PFF Viscosity 10 RPM 85 1024 1758 1778 FoamQuality Good Excellent Excellent Excellent Color white white white whiteOdor No odor No odor No odor No odor Shakability good Good Good GoodDensity 0.210 0.205 0.230 0.230 Hardness 11.50 16.50 15.46 14.93Greasiness Low Low Medium High

Procedure 08: Mineral oil was heated to ˜60 C, followed by the additionof glycerol monostearate until fully dissolved. The mixture was cooledslowly to 40-45° C. Cyclomethicone 5-NF was added with vigorousagitation at 40-45° C. The mixture was cooled to room temperature.

Procedure 09; 010; 011: Mineral oil was heated to ˜60° C., followed bythe addition of glycerol stearate until fully dissolved. The mixture wascooled rapidly to 30° C. using an ice bath. Cyclomethicone 5-NF wasadded with vigorous agitation at 30° C. The mixture was cooled to roomtemperature while stirring.

Foam quality: Light mineral oil using the slow cooling procedure,produced foam which was qualified as good compared to excellent in thefast cooling. Mixtures of the two produced high quality foam.Incorporation of light Mineral Oil improved foam quality.

These formulations were graded and placed on skin to determine impact onfeeling. Scale was as follows: High—unpleasant greasy feeling;Medium—bearable medium greasy; Low—pleasant feeling. When light mineraloil was the major component, the foam was less greasy compared to foamsin which heavy mineral oil was used in the high percentage.

Density—No major differences in density were observed. However, whenusing light solely or in combination, density is lower.

Viscosity—Interestingly when light mineral oil was the only oil used inthe slow procedure, separation was detected in the PFF and its viscositywas extremely low. The presence of light mineral oil reduced theviscosity of the PFF compared to heavy mineral oil.

When light mineral oil was used in comparison to heavy mineral oil, thefoam quality was high. However, the PFF demonstrated low viscosity andseparation of oil and silicone components. When a combination of heavyand light was used in ratios 1:1 and 1:2. respectively, the viscosityincreased and the foam demonstrated high quality and enhanced feeling.

Example 18 Comparison Between Heavy Mineral Oil and MCT Oil

Ingredients 18C 20C 31 (I) Rapid cooling (I) Rapid to (I) Rapid to to40-45° C., 40-45° C. (II) 40-45° C. (II) (II) RT Rapid to RT Rapid to RTHeavy Mineral Oil 84.28 MCT Oil 84.28 Octyldodecanol 84.00 Glycerolmonostearate 3.92 3.92 4.00 Cyclomethicone 5-NF 9.80 9.80 10.00Clindamycin Phosphate 2.00 2.00 2.00 Total 100.00 100.00 100.00Propellant(propane + 12.00 12.00 12.00 butane + isobutene) A46 RESULTSPFF Viscosity (10 RPM) 767.84 1095.77 146.97 FOAM Foam quality GoodGood- Fairly Good Color White White White Odor No odor No odor No odorShakability Good Good Good Density 0.103 0.085 N/M Collapse Time (36C.-Sec.) >300/FG 100/F N/M Bubble Mean Size (Mm) 89.00 N/M N/M BubblesAbove 500 Mm (%) 0.00 N/M N/M N/M = Not measured

Procedure for 18C—see example 1

Procedure for 20C—MCT oil was heated to about 50-55° C. followed by theaddition of glycerol stearate until fully dissolved. The mixture wascooled rapidly to about 40-45° C. Cyclomethicone 5-NF was added withvigorous agitation and cooled rapidly to room temperature. API was addedwith stirring.

Procedure for 31: Octyldodecanol was heated to about 50-55° C. followedby the addition of glycerol stearate until fully dissolved. The mixturewas cooled rapidly to about 40-45° C. Cyclomethicone 5-NF was added withvigorous agitation and cooled rapidly to room temperature. ClindamycinPhosphate was added with stirring.

Replacement of mineral oil by MCT oil does not significantly influencefoam quality but substituting octyldodecanol does result in a foamquality reduction. Interestingly, collapse time with mineral oil issubstantially longer.

Example 19 Heavy and Light Mineral Oil Mixture and Silicone Carrier withSolid Fatty Alcohol

Ingredient name 002 Procedure Rapid to 40-45° C. Light Mineral oil 25.00Heavy mineral oil 54.00 Glycerol monostearate 6.50 Cyclomethicone 5-NF10.00 Myristyl Alcohol 2.00 Total: 97.50 Propellant AP-70 8.00 ResultsFoam Quality Excellent Color White Odor No Odor Shakability GoodCollapse time >180 sec/G* FTC results Quality Good Color White Odor Noodor Shakability Good Density [g/mL] 0.079 Collapse time at 36° C. >180(sec)

Light mineral oil, heavy mineral oil and Myristyl Alcohol were mixed andheated to 60-65° C. followed by the addition of glycerol stearate untilfully dissolved. The mixture was cooled rapidly to about 40-45° C.Cyclomethicone 5-NF was added with vigorous agitation and cooled rapidlyto 5-10° C.

Mixed mineral oil plus silicone oil with added solid fatty alcoholprovides excellent stable low density, shakable, breakable foam, whichis capable of being subjected to four freeze-thaw (FTC) cycles. Thecarrier can be used to provide a homogenous suspension of API as well asdissolving oil soluble API's. As shown above, the carrier produces astable, breakable foam which does not collapse after more than 3 minutesin the absence of applied mechanical shear force.

Example 20 Oil: PPG-15 Stearyl Ether, Octyldododecanol and SiliconeCarrier Using the Rapid Cooling Procedure

Ex 22 PART A)

001P 002P 003P 004P 005P 006P 007P Ingredient name % w/w % w/w % w/w %w/w % w/w % w/w % w/w PPG-15 Stearyl Ether 15.00 15.00 15.00 15.00Octyldodecanol 6.00 4.00 4.00 6.00 Light mineral oil 25.00 25.00 25.0023.00 22.00 22.50 25.50 Heavy mineral oil 50.90 50.90 51.90 31.40 38.5038.50 31.40 Glycerol 4.00 4.00 4.00 10.00 6.00 4.00 8.00 monostearateMyristyl alcohol 2.40 2.40 Paraffin 51-53 1.50 Cetostearyl alcohol 2.502.00 Stearyl alcohol 1.00 1.00 Cyclomethicone 5-NF 10.00 10.00 10.003.00 3.00 3.00 3.00 Triethanol amine 0.10 0.10 0.10 0.10 0.10 0.10 0.10PPG 15 stearyl ether 8.9604 Capric caprylic 8.9604 8.9604 8.9604 8.96048.9604 8.9604 triglyceride Butyleated 0.0396 0.0396 0.0396 0.0396 0.03960.0396 0.0396 hydroxytoluen Total: 100.00 100.00 100.00 100.00 100.00100.00 100.00 Propellant AP-70 8.00 8.00 8.00 8.00 8.00 8.00 8.00 Foamappearance of FG FG FG Excellent Good Good- Excellent placebo (withoutAPI) Shakability of placebo Good Good Good Not shakable Good GoodModerate (without API) but flowable

Surprisingly it appears that the presence of about 9% Capric/caprylictriglyceride (MCT oil) reduces the foam quality to fairly good and itmay be that a small amount of Triethanolamine also has a negative impacton foam quality. Addition of PPG-15 stearyl ether with octyldodecanolinto the formulation appears to counteract this capric caprylictriglyceride effect. It may be that PPG-15 Stearyl Ether orOctyldodecanol are effective alone.

Further results for formulations 005 and 007 in which the API is presentare provided in the tables below in Parts C TO F:

Ex 20 PART B)

005 007 Ingredient name % w/w % w/w PPG-15 Stearyl Ether 15.00 15.00Octyldodecanol 4.00 6.00 Light mineral oil 22.00 25.50 Heavy mineral oil38.50 31.40 Glycerol monostearate 6.00 8.00 Myristyl alcohol 2.40Cetostearyl alcohol 2.00 Stearyl alcohol Cyclomethicone 5-NF 3.00 3.00Triethanol amine 0.10 0.10 Capric caprylic 8.9595 8.9595 triglycerideButyleated 0.0396 0.0396 hydroxytoluene Calcitriol 0.0009 0.0009 Total:100.00 100.00 Propellant AP-70 8.00 8.00Ex 20 PART C) Foam Product (Pressurized Formulation)

Product homogeneous Collapse and redispersibile after Formu- Shak-Appearance Density time at Hardness shaking (when viewed in lationability Quality* Color Odor [g/mL)] 36° C. [sec] [g] pressurized glassbottle) 005 1 E 1 2 0.104 180 13.43 Yes 007 2 E 1 2 0.105 >300 16.50 Yes*After at least 24 hours following manufactureEx 20 PART D) Short Term Physical Stability, Test Results

Appearance Quality Color Odor Shakability (scoring) (scoring) (scoring)Density (g/mL) Formu- 3 weeks, 4 weeks, 3 weeks, 3 weeks, 3 weeks,lation T-0 FTC 40° C. T-0 FTC 40° C. T-0 FTC 40° C. T-0 FTC 40° C. T-0FTC 40° C. 005 1 2 2 E G FG 1 1 1 2 2 2 0.104 0.111 0.112 007 2 2 2 E GG 1 1 1 2 2 2 0.105 0.112 0.112Ex 20 PART E) Short Term Physical Stability, Test Results—Continued

Product homogeneous and Collapse redispersible after Corrosion & time(sec) shaking(when viewed in deterioration Formu- 3 weeks, pressurizedglass bottle) 3 weeks, lation T-0 40° C. T-0 3 wk 40° C. 005 180 180 YesYes None observed 007 >300 >300 Yes Yes None observedEx 20 PART F) The codes for foam color, foam odor and shakability are asprovided below:

Score Foam Color White to faint yellow (acceptable) 1 Darker than yellow(not acceptable) 0 Foam Odor No odor 2 Very faint -Typical odor 1Noticeable odor 0 Shakability Good shakability (acceptable) 2 Moderateshakability (acceptable) 1 Not shakable (not acceptable) 0Ex 20 PART G) Formulations 5, 6, 7 are preferred and show how relativelysmall changes in the composition can substantially affect the foamproduced. The data also demonstrate the stability of the formulationsand the ability of the formulations to withstand strenuous environmentalconditions.

A batch of formulation 007 was prepared. Prior to the cooling step thebatch was divided into two. One part was subjected to fast cooling byimmersing the container into an ice bath with stirring to reach roomtemperature whilst another part was merely left to cool in the room toroom temperature with stirring without any external bath.

Cf Section 3 below 007 007 Procedure Slow cooling Rapid cooling to25-30° C. to 25-30° C. Ingredient name % w/w % w/w PPG-15 Stearyl Ether15.00 15.00 Octyldodecanol 6.00 6.00 Light mineral oil 25.50 25.50 Heavymineral oil 31.40 31.40 Glycerol monostearate 8.00 8.00 Cetostearylalcohol 2.00 2.00 Cyclomethicone 5-NF 3.00 3.00 Triethanol amine 0.100.10 Stock Solution (as per 9.00 9.00 Example 12) Total: 100.00 100.00Propellant AP-70 8.00 8.00 Results PFF (before addition of propellant)Appearance Rich Milky Cream Cloudy Ointment Feel Creamy Oily OintmentFoam Quality E E Color white white Odor no odor no odor Shakability GoodGood Density [g/mL)] 0.110 0.105 Collapse time at 36 C. [sec] >180/G>180/G

Whilst the PFF was externally visually different (FIG. 1) and alsodisplayed a different feel there was no apparent difference in thephysical properties of the resultant foam after addition of propellantand release of the formulations from a sealed canister. Unexpectedly,the slow cooled formulation provided a cosmetically elegant creamy feelwhilst the fast cooled formulation was more oily and ointment like insensation. On a microscopic level whilst both PFF's contained somebubble or vesicle like structures the slow cooled formulation displayeda higher number of such bodies. These bodies had within them a bubblelike structure.

Section 4—Miscellaneous Example 21 Rate of Cooling Experiments

A 100 g batch of formulation was prepared in each case according to thecooling methods described herein. It is noted that larger batch sizeswill require a longer time duration for cooling using the same size andquantity ice bath and, accordingly, the rate of cooling will be slower.The rate of cooling can be increased by using a supercooled mixture ofwater, ice and salt or acid. Such mixtures can readily reachtemperatures of minus 10° C. Care is taken to ensure that theformulation is stirred rapidly and the temperature does not fall belowroom temperature. Thus, by simply having a larger temperature gradientrapid cooling can be accelerated. Lower temperatures can be achieved byusing a colder substance such as a slurry of dry ice provided their useis very carefully controlled such that the temperature does not fallbelow room temperature and that freeing is not induced. Other means ofimproving cooling, as known in the art can be used such a a coolingjacket through which is pumped cold water.

Part A—Rapid

The formulation 043 below was prepared and subjected to rapid cooling asfollows:

Ingredients 043-Rapid % w/w Heavy Mineral Oil 86.00 GlycerolMonostearate 4.00 Cyclomethicone 10.00 Control: 100.00 Propellant 16818.00

Manufacturing Procedure (Rapid Cooling Protocol):

Step 1: Mixing of Oily Ingredients and Surfactant

Heat up the Heavy mineral oil to 60-65° C.

Add Glycerol monostearate under mixing by homogenizer for 15-20 min.

Mix till completely dissolution. Allow to reach ˜65° C.

Step 2: Cooling of PFF

Cool down the PFF from Step 1 to 33-35° C. by plunging the containerinto an ice bath while stirring.

The time it took for the composition to cool to certain temperatures wasmeasured:

Temperature drop from 65° C. to 55° C.: 1 min 16 sec (7.9degrees/minute);

Temperature drop from 55° C. to 45° C.: 1 min 30 sec (6.7degrees/minute);

Temperature drop from 45° C. to 35° C.: 2 min 20 sec (2.2degrees/minute);

Step 3: Add Cyclomethicone by Mixing.

Continue Cooling down to the room temperature with stirring using theice bath.

Temperature drop from 35° C. to 25° C.: 2 min 30 sec (2.2degrees/minute);

Cool to room temperature Mix well the whole preparation for 15-20 min.

The formulation 043 below was prepared and subjected to slow cooling asfollows:

Part B

A second batch of composition (044-Slow) was prepared and cooledaccording to the slow cooling procedure described herein.

Ingredients 044-Slow % w/w Heavy Mineral Oil 86.00 Glycerol Monostearate4.00 Cyclomethicone 10.00 Control: 100.00 Propellant 1681 8.00

Manufacturing Procedure (Slow Cooling Protocol):

Step 1: Mixing of Oily Ingredients and Surfactant

Heat up the Heavy mineral oil to 60-65° C.

Add Glycerol monostearate under mixing by homogenizer for 15-20 min.

Mix until complete dissolution. Allow to reach ˜65° C.

Step 2: Cooling of PFF

Cool down the PFF from Step 1 to 33-35° C. by standing on air (i.e.,room temperature) by stirring.

The time it took for the composition to cool to certain temperatures wasmeasured: Temperature drop from 65° C. to 55° C.: 2 min 30 sec (2.2degrees/minute);

Temperature drop from 55° C. to 45° C.: 5 min 30 sec (1.8degrees/minute);

Temperature drop from 45° C. to 35° C.: 8 min 30 sec (1.2degrees/minute);

Step 3: Add Cyclomethicone by Mixing.

Continue cooling down to room temperature with stirring using the icebath.

Temperature drop from 35° C. to 25° C.: 26 min (0.4 degrees/minute);

Cool to room temperature. Mix well the whole preparation for 15-20 min.

Part C—Super fast cooling by insertion into alcohol—water circulatingbath at −10° C.

A batch of composition (046-Super Fast) was prepared and cooledaccording to the super fast cooling procedure described herein.

Ingredients 046 Super Fast % w/w Heavy Mineral Oil 86.00 Glycerolmonostearate 4.00 Cyclomethicone 10.00 Control: 100.00 Propellant 16818.00

Manufacturing Procedure (Super Fast Cooling Protocol):

Step 1: Mixing of Oily Ingredients and Surfactant

Heat up the Heavy mineral oil to 65° C. Allow to reach ˜65° C.

Add glycerol monostearate under mixing by homogenizer for 15-20 min.

Mix till completely dissolution. Allow to reach ˜65° C.

Step 2: Cooling of PFF

Cool down the PFF from Step 1 to 33-35° C. by plunging the containerinto an Lauda RE206 alcohol-water bath at (−10° C.) by plunging thecontainer into an alcohol-water circulating bath at −10° C. whilestirring.

The time it took for the composition to cool to certain temperatures wasmeasured:

Temperature drop from 65° C. to 55° C.: 1 min (10 degrees/minute)

Temperature drop from 55° C. to 45° C.: 1 min (10 degrees/minute)

Temperature drop from 45° C. to 35° C.: 1 min 30 sec (6.7degrees/minute)

Add Cyclomethicone by mixing.

Continue cooling down to the room temperature (23° C.) with stirringusing the alcohol water bath.

Temperature drop from 35° C. to 25° C. (RT): 2 min 30 sec (4degrees/minute)

Cool to room temperature. Mix well the whole preparation for 15-20 min.

Conclusions:

All formulations -043 and -044 and -046 were tested for foam quality.Rapid and super rapid produced good quality foam whilst slow coolingproduce foam of a lower quality, namely fairly good. These experimentsclearly show that the foam quality of formulations prepared by fastcooling and extremely fast cooling methods were better than thatproduced by the slow cooling method.

The total time to cool from 65° C. to room temperature for rapid coolingwith a regular ice bath took 7 minutes 36 seconds and was approximatelyalmost six fold faster overall when compared to slow cooling, which took42 minutes 30 seconds. The initial temperature drop to 55° C. took lessthan half the time than that for slow cooling. Each stage thereaftertook progressively longer for slow cooling. When a super cool bath wasused the cooling rate was reduced by about 25% to six minutes whencompared to the rapid procedure.

Section 5—Rapid Collapse Prior Art Example Example 24

US 2005/0287081 provides examples of high silicone lipophilicformulations with liquid surfactant and beeswax. The formulation ofExample 1 of the “081” application set out below was made in duplicateas described below.

All ingredients are weighed in a vessel and it is heated to 70-75° C.,and mixed well until uniform. It is then cooled to ambient andpressurized in an aerosol can with Hydrofluorocarbon in the ratio: Base:85%, Propellant: 15%.

Ingredient % w/w Caprylic/Capric Triglyceride 20.00 Mineral Oil 8.00Cyclomethicone 5-NF 31.25 Sorbitan Oleate 5.00 Polyoxyl 40 HydrogenatedCastor Oil 4.00 Petrolatum 30.00 Beeswax 0.75 Hydrogenated Castor Oil1.00

The foam quality for the formulation prepared accordingly to theExamples of US 2005/0287081, in both cases with propellant AP70, wasfair (which is not considered acceptable for pharmaceuticalformulations). Notably, the foam started to collapse almost immediatelyupon dispensing, and fully collapsed after approximately 10 seconds. Theformulation was prepared again, with a different propellant (Dymel),with very similar results.

Discussion

Surprisingly single phase mixture of a surfactant-glycerol monostearateand oil were capable of producing high foam quality. glycerolmonostearate and other fatty acid monoesters are not efficientemulsifiers as sited from Handbook of pharmaceutical excipients 5^(th)edition. In some embodiments, when glycerol monostearate was replaced byother surfactants, foam quality was reduced, emphasizing the effect ofthis unique surfactant.

As described herein foamable carriers containing glycerol monosterate,which is highly soluble in mineral oil, produced foam of high quality.Interestingly, foamable carriers containing glycerol palmitostearate,which is not soluble in oil also produced high quality foam. Indeedmixing mineral oil and glyceryl palmitostearate formed two phases incomparison to a single phase GMS/oil system. Nevertheless, glycerolpalmitostearate is an esterification product of stearic and palmiticacids. Therefore it may be assumed that partial solubility may bedemonstrated. Moreover, without being bound to any theory, it may beassumed that addition of cyclomethicone to a compositions containingglycerol palmitostearate may increase the solubility of glycerolpalmitostearate in oil. This is in concordance with the common polarityindex of both emollients: mineral oil approximately 43.7 mN/m andcyclomethicone approximately 20 mN/m. Mixing of both increases the polarenvironment required for enhanced solubility of palmitostearate.

The addition of a silicone to the oil and glycerol monostearatemixture—whilst having defoaming and destabilizing properties—was able tolower surface tension to provide the foam with an improved and elegantfeel and a drying effect.

Surprisingly cyclomethicone can act to improve foam quality at certainratios with oil and yet at other ratios it acts to destroy the foamstructure. Unexpectedly, when cyclomethicone was introduced intoformulations with some of the other surfactants (other than glycerolmonostearate) it slightly improved foam quality compared to foamproduced from the same formulations without cyclomethicone.

Foam quality depends on spatial structure of silicones: cyclic andhighly substituted linear silicones create a stearic hindrance and maynot penetrate to any significant or substantial degree into the stablemineral oil/Glycerol monostearate structure.

Apparently, in order to produce foam of quality, the selection ofsurfactant is important and the ratio between Glycerol monostearate andCyclomethicone 5-NF in formulation can be approximately in the range of1:1 to 1:4 respectively.

The manufacturing procedure is highly significant. Introduction of arapid cooling step improved foam quality when compared to the foam ofthe same formulation produced using slow cooling. Thus, rapid cooling ofoil/silicone single phase formulations unexpectedly results in theproduction of high quality foam. It was noted that rapid cooling ofmineral oil/silicone/Glycerol monostearate mixture from 60° C. tominimum 30° C. significantly and visibly improved foam quality. Moreovera continuum of cooling step following the addition of silicones ofstearic hindrance improves foam quality. Changes (visual) in thepre-foam formulation appearance and in its viscosity were surprisinglynoted depending on whether fast or slow cooling was used.

Not only was fast cooling preferred but addition of the silicone issurprisingly preferred the closer the temperature is to roomtemperature. In other word Silicone is best added after the rapidcooling is completed.

Mixtures of oils were unexpectedly better. Also mixtures were lesssusceptible to the destabilizing effects of silicones. Similarlyformulations with many ingredients were less susceptible to the effectsof silicones than formulations with few ingredients—perhaps withoutbeing bound by any theory there are more options available to thesilicones other than say mineral oil/surfactant arrangements.

Section 6—Prophetic Examples Example 25 Prophetic

a) Foamable Oil and Silicone Compositions, Containing a Steroid Drug

The following steroids can be included in carriers, compositions andfoams: betamethasone valerate 0.12%, clobetasol propionate 0.05%,betamethasone dipropionate 0.05%, fluocinolone acetonide 0.025%,hydrocortisone acetate 0.5% and hydrocortisone butyrate 0.1%.

b) Foamable Oil and Silicone Compositions, Containing a Vitamin and aSteroid Drug

Additionally, one or more of the following vitamins can be included inthe carriers, compositions and foams: vitamin C (ascorbic acid) between0.1 and 5% say, 0.1% 1%, 2% 3%, 4%, or 5%; vitamin C (magnesium ascorbylphosphate) 3%, retinol 1%, retinoic acid 0.1%, niacinamide 2% andtocopherol 1% and Vitamin K. between 0.1 and 2% say, 0.1% or 1% or 2%.

Example 18 Prophetic Foamable Vitamin Compositions with an AdditionalTherapeutic Agent

Foamable vitamin compositions at either say 1%, 2%, 3%, 4%, or 5%, byweight of composition are made up with an active agent and added to anyof the compositions illustrated in Examples 1-12 and 16 below with orwithout the active agents listed in the Examples wherein the percentageamount of solvent is reduced by an approximately equivalent amount byweight in the composition.

Example 26 Prophetic Foamable Therapeutic Agent Compositions

More particularly exemplary concentrations of additional therapeuticagents in foamable compositions are set out in the table below. Eachactive agent is added into, for example, any of the carriers listed inany of Examples 1-12 above and 16 below in a therapeutically effectiveconcentration and amount with or without the active agents listed in theExamples. The methodology of addition is well known to those of the art.The composition is adjusted in each case so that it is made up to 100%w/w as appropriate by solvent.

Exemplary Concentrations of Examples of Active Agents

Exemplary Additional therapeutic agent Concentration Exemplary UseHydrocortisone acetate 1% Steroid responsive inflammation and psoriasisor atopic dermatitis Betamethasone valerate 0.1%   Clobetasol propionate0.05%   Acyclovir 5% Viral infection, herpes Ciclopirox 1% Fungalinfection, seborrhea, dandruff, Clindamycin 2% Bacterial infection,acne, rosacea, Azelaic acid 15%  Acne, rosacea, pigmentation disorderand various dermatoses Metronidazol 0.25%-2%   Rosacea, bacterialinfections and parasite infestations Diclofenac 1% Osteoarthritis, jointpain Tacrolimus 0.2%   Atopic dermatitis, eczema and inflammationBenzoyl peroxide 1%-10% Acne Alpha-hydroxy acids 1%-20% Aging, wrinklesSalicylic acid 1%-10% Acne Hydroquinone 1%-10% Pigmentation disordersCaffeine 1%-10% Anti Cellulite Coenzyme Q 10 0.1%-10%  Aging,pigmentation Clotrimazole 1% Fungal infection Lidocaine base 2% Localanesthetic Terbinafine HCL 1% Fungal infection Gentamycin 0.1%  Bacterial skin infections, burns or ulcers Dexpanthenol 5% Wounds,ulcers, minor skin infections Urea 5-10%   Emollient and keratolyticAtopic dermatitis, eczema, ichthyosis and hyperkeratotic skin disordersAmmonium lactate  12%-17.5% Dry scaly conditions of the skin includingichthyosis Povidone-iodine 10%  Antimicrobial - antiseptic Calcitriol~0.005%      Psoriasis Calcipotriol ~0.005%      Psoriasis Imiquimod 5%Treatment of external genital and perianal warts, superficial basal cellcarcinomas and actinic keratoses Estradiol 0.005%    Treatment ofvaginal atrophy caused by menopause Minocycline Hydrochloride 1%Treatment of acne Doxycycline Monohydrate 1% Treatment of acneDoxycycline Hyclate 1% Treatment of acne

The above examples represent different drug classes and it is to beunderstood that other drugs belonging to each of the classes representedabove may be included and used in the compositions in a safe andeffective amount.

Example 27 Prophetic Foamable Compositions Comprising Microsponges

A microsponge is added into, for example, any of the carriers listed inany of Examples 1-11 above. The microsponges are loaded with activeagents in a therapeutically effective concentration and amount and themicrosponges are incorporated into one of the said carriers. Themethodology of addition is known to those of the art. The composition isadjusted in each case so that it is made up to 100% w/was appropriate bysolvent. Care should be taken in selecting and preparing the formulationsuch that the microsponges are distributed substantially homogenouslyand so that any aggregation of microsponges is minimized such that theydo not block the canister valve and thereby prevent release of foam.

Example 27A Prophetic Hydrophobic Solvent Foamable FormulationComprising Microsponges Loaded with Active Agent

Ingredients % w/w % w/w Drug Microsponge ® 10 10 Heavy Mineral Oil To100 Light Mineral Oil To 100 Volatile Silicone* 1-25 1-25 Glycerolmonostearate 1-5  1-5  Propellant 12.00 12.00 *volatile silicone can befor example Cyclomethicone.

This prophetic formulation can be adapted for a high range ofhydrophobic solvent content of up to about 95%.

The amount of microsponges may be varied from about 1% to about 25% ofthe formulation by increasing or decreasing the amount of thehydrophobic solvent.

Any active agent suitable for loading in microsponges may be used.Non-limiting examples are benzyl peroxide, tretinoin, hydroquinone andthe like or any of the active agents described in Examples 1 to 11above.

In an embodiment the microsponges are loaded with one or more vitaminsor with one or more flavonoids or combinations thereof.

The liquefied or gas propellant can be added at a concentration of about3% to about 35%, for example in a ratio of carrier composition topropellant of at least about 100:3, or about 100:3 to about 100:35.

It is appreciated that certain features, which are, for clarity,described in the context of separate embodiments, may also be providedin combination in a single embodiment. Conversely, various features,which are, for brevity, described in the context of a single embodiment,may also be provided separately or in any suitable subcombination.Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.

What is claimed is:
 1. A waterless foamable pharmaceutical composition,comprising a foamable carrier and at least one liquefied or compressedgas propellant, wherein the foamable carrier comprises: a) about 60% toabout 95% by weight of the foamable carrier of at least one liquid oilselected from the group comprising a mineral oil, a MCT oil, a liquidparaffin, a vegetable oil, an essential oil, an organic oil, a lipid, ora mixture of two or more thereof comprising about 60-90% mineral oil; b)about 0.5% to about 15% by weight of the foamable carrier of a silicone;and c) about 0.01% to about 25% by weight of the foamable carrier of atleast one foam stabilizing agent comprising glyceryl monostearate;wherein the foamable carrier is a single phase; wherein the foamstabilizing agent optionally comprises at least one foam adjuvant;wherein the silicone is selected from the group consisting of a siloxanecompound having 4-6 Si—O groups in its backbone, a cyclomethicone, acyclotetrasiloxane, a cyclopentasiloxane, a cyclohexasiloxane, a phenyltrimethicone, a stearyl dimethicone, a cetyl dimethicone, a caprylylmethicone, a PEG/PPG 18/18 dimethicone, a dimethiconol, and a mixture ofany two or more thereof; wherein the composition is essentially free ofwater; wherein the ratio of the foamable carrier to the propellant is100:3 to 100:35; wherein the resultant foam does not collapseimmediately upon release and is breakable on mechanical shear; whereinthe waterless foamable pharmaceutical composition comprises aminocycline or a doxycycline or both; and wherein the minocycline or thedoxycycline is stable for at least 3 weeks at 25° C. in the waterlessfoamable pharmaceutical composition.
 2. The waterless foamablepharmaceutical composition of claim 1, wherein the oil is a mixture ofheavy mineral oil and light mineral oil having a weight ratio from about1:5 to about 25:1.
 3. The waterless foamable pharmaceutical compositionof claim 1, further comprising an emollient selected from the groupconsisting of cocoglycerides, PPG 15 stearyl alcohol, octyldodecanol,isopropyl myristate, diisopropyl adipate, cetearyl octanoateisohexadecanol, diisopropyl adipate, and a mixture of any two or morethereof.
 4. The waterless foamable pharmaceutical composition of claim1, further comprising a solid wax or solid oil selected from the groupconsisting of a solid paraffin, a hydrogenated oil, a hydrogenatedemollient, palmitic acid, stearic acid, arachidic acid, behenic acid,and a mixture of any two or more thereof.
 5. The waterless foamablepharmaceutical composition of claim 1, wherein the foam adjuvantcomprises a fatty alcohol and a fatty acid.
 6. The waterless foamablepharmaceutical composition of claim 1, wherein the foam stabilizingagent is in combination with a foam adjuvant selected from the groupconsisting of stearyl alcohol, cetyl alcohol, cetostearyl alcohol,myristyl alcohol, palmitoleyl alcohol, arachidyl alcohol, benhylalcohol, and a mixture of any two or more thereof.
 7. The waterlessfoamable pharmaceutical composition of claim 1, wherein the foamstabilizing agent is in combination with a foam adjuvant, wherein saidfoam adjuvant comprises oleyl alcohol.
 8. The waterless foamablepharmaceutical composition of claim 1, wherein the weight ratio of foamstabilizing agent to silicone ranges from about 1:1 to about 1:4.
 9. Thewaterless foamable pharmaceutical composition of claim 1, comprising byweight of the foamable carrier: a) about 60-90% mineral oil; b) about1-15% of a silicone, where the silicone is selected from the groupconsisting of a cyclomethicone, a cyclohexasiloxane, acyclopentasiloxane, a cyclytetrasiloxane, a dimethiconol, a phenyltrimethicone, a stearyl dimethicone and a mixture of any two or morethereof; c) about 1-8% glycerol monostearate; and d) about 1-8% myristylalcohol or cetostearyl alcohol.
 10. A waterless foamable pharmaceuticalcomposition according to claim 1, further comprising an active agent inaddition to a minocycline and or a doxycycline.
 11. The waterlessfoamable pharmaceutical composition according to claim 10, wherein theactive agent is selected from the group consisting of active herbalextracts, acaricides, age spot removing agents, keratose removingagents, allergen, analgesics, local anesthetics, antiacne agents,antiallergic agents, antiaging agents, antibacterials, antibioticagents, antiburn agents, anticancer agents, antidandruff agents,antidepressants, antidermatitis agents, antiedemics, antihistamines,antihelminths, antihyperkeratolyte agents, antiinflammatory agents,antiirritants, antilipemics, antimicrobials, antimycotics,antiproliferative agents, antioxidants, anti-wrinkle agents,antipruritics, antipsoriatic agents, antirosacea agents, antiseborrheicagents, antiseptic, antiswelling agents, antiviral agents, anti-yeastagents, astringents, topical cardiovascular agents, chemotherapeuticagents, corticosteroids, dicarboxylic acids, disinfectants, fungicides,hair growth regulators, hormones, hydroxy acids, immunosuppressants,immunoregulating agents, insecticides, insect repellents, keratolyticagents, lactams, metals, metal oxides, mitocides, neuropeptides,non-steroidal anti-inflammatory agents, oxidizing agents, pediculicides,photodynamic therapy agents, retinoids, scabicides, self tanning agents,skin whitening agents, vasoconstrictors, vasodilators, vitamin A,vitamin A derivatives, vitamin B, vitamin B derivatives, vitamin C,vitamin C derivatives, vitamin D, vitamin D derivatives, vitamin E,vitamin E derivatives, vitamin K, vitamin K derivatives wound healingagents, wart removers, and a mixture of any two or more thereof.
 12. Thewaterless foamable pharmaceutical composition according to claim 10,wherein the additional active agent is selected from the groupconsisting of acyclovir, azaleic acid, clindamycin phosphate,pimicrolimus, diclofenac potassium, calcipotriol, calcitriol, vitamin Aacetate, betamethasone 17-valerate, alpha tocopherol, imiquimod,ciclopiroxolamine, and a mixture of any two or more thereof.
 13. Amethod for treating or ameliorating a disorder comprising administeringto a target site a pharmaceutically effective amount of the waterlessfoamable pharmaceutical composition according to claim 1, wherein thetarget site is selected from the group consisting of the skin, a bodycavity, a mucosal surface, the nose, the mouth, the eye, the ear canal,the respiratory system, the vagina, and the rectum.
 14. A methodaccording to claim 13, wherein the waterless foamable pharmaceuticalcomposition comprises at least one additional active agent.
 15. Thewaterless foamable pharmaceutical composition according to claim 1,wherein the resultant foam displays all of the followingcharacteristics: a. does not collapse immediately upon release; b. isbreakable on mechanical shear; c. has a viscosity below about 13,000cps; d. has an average bubble size below 200 microns; e. has a hardnessbetween about 5 to about 35; f has a collapse time in excess of about180 seconds; and g. has a density below about 0.2g/ml.
 16. The waterlessfoamable pharmaceutical composition according to claim 1, furthercomprising up to 5% or about 5% by weight of at least one polymericagent alone or in combination with a foam adjuvant.
 17. The waterlessfoamable pharmaceutical composition according to claim 10, wherein thefoamable carrier including the active agent is a homogenous suspension.18. A method for preparing a single phase waterless foamablepharmaceutical composition according to claim 1, the method comprisingthe steps of either: (a) combining the at least one liquid oil with theat least one foam stabilizing agent at a temperature of at least 50° C.or about 50° C.; (b) rapidly cooling the combination of one liquid oiland at least one foam stabilizing agent to less than 40° C.; (c) addingthe silicone and the minocycline or the doxycycline or both to thecooled combination to make a prefoam formulation; and (d) combining theprefoam formulation with a compressed gas propellant in a weight ratioof 100:3 to 100:35 to form the waterless foamable pharmaceuticalcomposition; or (i) preparing a prefoam formulation by combining at atemperature of at least 50° C. or about 50° C.: the at least one liquidoil; the silicone; and the at least one foam stabilizing agent; (ii)rapidly cooling the prefoam formulation to less than 40° C.; (iii)adding the minocycline or the doxycycline or both to the prefoamformulation; and (iv) combining the prefoam formulation with acompressed gas propellant in a weight ratio of 100:3 to 100:35 to formthe waterless foamble pharmaceutical composition.
 19. The method ofclaim 18, wherein the cooling step is carried out by placing thecombination of one liquid oil and at least one foam stabilizing agent inan ice bath, or in an alcohol water bath, or in a water bath or jacket.20. The method of claim 18, wherein the combination of one liquid oiland at least one foam stabilizing agent is cooled at a rate of at least5 degrees/minute or about 5 degrees/minute.
 21. The method of claim 18,wherein the combination of one liquid oil and at least one foamstabilizing agent is cooled to a temperature of at least 25° C. or about25° C.
 22. The method of claim 18, wherein the foam stabilizing agent isa monoglyceride, diglyceride, or triglyceride, or a mixture of any twoor more thereof, wherein the side chain of the monoglyceride,diglyceride, or triglyceride is a saturated hydrocarbon.
 23. The methodof claim 18, wherein the foam stabilizing agent is glycerol monostearateand glycerol palmitostearate.